Abstract
Indole alkaloids, predominantly found in plants, are a large group of natural product-derived compounds characterized by a remarkable chemical diversity associated with significant biological properties. Among these, terpenoid indole alkaloids are the largest group of secondary metabolites. Tabernaemontana species (Apocynaceae) are widely distributed in tropical and subtropical regions of the world and used in traditional medicine to treat a variety of illnesses, including tumours. These species biosynthesize large quantities of structurally complex monoterpene indole and bisindole alkaloids. Given the compelling biological properties of indole alkaloids, the phytochemical study of Tabernaemontana species has been widely addressed to identify potential anticancer compounds. Several indole alkaloids have shown antiproliferative effect due to different mechanisms, namely by inducing apoptosis or arresting cell cycle, in diverse cancer cell lines, including multidrug-resistant phenotypes. This review primarily aims to underscore the anticancer activity of indole and bisindole alkaloids isolated from several Tabernaemontana species. Moreover, our recent contributions to the field are also highlighted, focusing on the study of Tabernaemontana elegans. The anticancer evaluation, namely the reversion of P-glycoprotein-mediated multidrug resistance, of two sets of monoterpene indole alkaloid derivatives, obtained by modification of some functional groups of two major monoterpene indole alkaloids, is reviewed, as well as the results obtained for a derivative that targeted homologous recombination DNA repair defects.
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Introduction
Alkaloids are nitrogen-containing compounds that belong to one of the largest groups of natural products and are often linked to significant biological properties. The designation alkaloid (alkali-like) derives from their inherent basic properties, owing to the presence of one or more nitrogen atoms in their structures, commonly in heterocycles. Due to their frequently varied and complex scaffolds, alkaloids are usually classified into diverse classes, such as indoles, quinolines, isoquinolines, pyrrolidines, piperidines, based on their nitrogen-containing structure (Dewick 2009).
In alkaloid biosynthesis, nitrogen atoms predominantly derive from an amino acid precursor, whose carbon skeleton is usually preserved in the alkaloid scaffold in large extension, leading to a different classification (Dewick 2009; Dey et al. 2020).
Terpenoid indole alkaloids constitute the largest subgroup of alkaloids in plants, with many being identified within the Apocynaceae, Loganiaceae, and Rubiaceae families. Monoterpene indole alkaloids have as precursor the amino acid L-tryptophan, whose decarboxylation originates tryptamine, which, generally, reacts with the terpenoid aldehyde secologanin evidenced by a C-9 or C-10 terpenoid moiety incorporated in their structures. According with the rearrangement of the terpenoid part, three main structural types of monoterpene indole alkaloids, namely of the corynanthe, aspidosperma and iboga-type, are formed (Figs. 1 and 2). Coupling reactions between monomeric indole alkaloids give rise to bisindole alkaloids (Dewick 2009).
The genus Tabernaemontana belongs to the Apocynaceae family and comprises more than 100 species, distributed as shrubs or small trees in tropical and subtropical regions of the world, including Africa, America, and Asia. Their species are characterised for producing a wide variety of monoterpene indole and bisindole alkaloids with high structural complexity. Tabernaemontana species have long been used in traditional medicine, for treating several diseases, including tumours and inflammation (Van Beek et al. 1984; Marinho et al. 2016). Monoterpene indole alkaloids have emerged as pivotal agents in cancer treatment, with compounds such as vinblastine and vincristine (Fig. 3), originally isolated in the 1950s from the Madagascar periwinkle Catharanthus roseus. These alkaloids stand as pioneering plant-derived anticancer agents approved for clinical use. Due to their potent cytotoxic activity, new semisynthetic analogous of these alkaloids were prepared and still being in used in clinical settings, namely vinorelbine, vindesine and vinflunine (Fig. 3) (Silvestri 2013; Banyal et al. 2023). Some of these semisynthetic analogues are again in clinical trials to extend their anticancer activity to new types of cancers. In this way, vinorelbine is currently in a phase III trial, for the treatment of patients with rhabdomyosarcoma, a rare type of cancer that may affect mostly the muscles. The aim is to compare its effect when combined with other anticancer agents, including vincristine (Allen-Rhoades 2024). Moreover, the use of vinorelbine as a second-line treatment of malignant pleural mesothelioma, a rare type of cancer that affects the pleura, has also been in a randomised phase II trial (Fennell et al. 2022) (Fennell 2021). Another example of vinca alkaloids that have been the subject of clinical trials against several new types of cancer, namely advanced breast cancer, is the fluorinated derivative vinflunine (Binghe 2019).
In addition, these compounds not only exhibit great structural diversity (O’Connor and Maresh 2006; Song et al. 2023) but also exert their anticancer efficacy through modulation of diverse signalling pathways, encompassing the inhibition of cancer cell proliferation (Kang et al. 2022), cell cycle arrest (Du et al. 2023), and induction of apoptosis (Paterna et al. 2015; Fang et al. 2019). Monoterpene indole alkaloids have also demonstrated therapeutic potential in addressing one of the most challenging obstacles in cancer chemotherapy, the multidrug resistance (MDR) (Cardoso et al. 2021b). This multifactorial phenomenon is characterized by the ability of drug resistant tumours to exhibit simultaneous resistance to several structurally and functionally unrelated chemotherapeutic agents. The development of inhibitors, or modulators, targeting ABC transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2), has been considered a pragmatic strategy for reinstating drug sensitivity in resistant cells when co-administered with anticancer drugs (Feyzizadeh et al. 2022). Another frequently explored approach, known as collateral sensitivity, involves the identification of compounds exhibiting higher cytotoxicity against MDR cells compared to parental cells (Pluchino et al. 2012). Recent investigations have unveiled that monoterpene indole alkaloids and some of their derivatives possess enhanced anticancer properties, namely as selective P-gp (Cardoso et al. 2021a) or MRP1 inhibitors, and with significant collateral sensitivity effect (Paterna et al. 2018). For all these reasons, monoterpene indole alkaloids have been attracting the attention of the scientific community as promising candidates for the development of new anticancer therapeutics.
In this work, the anticancer activity of indole and bisindole alkaloids from Tabernaemontana species is reviewed. Aiming at summarizing our contribution in the study of these species, the anticancer evaluation of two sets of monoterpene indole alkaloid derivatives, obtained by modification of some functional groups of two major monoterpene indole alkaloids, isolated from Tabernaemontana elegans, is also summarized.
The literature search was performed on Web of Science, ScienceDirect, PubMed, Scopus, and Google Scholar, covering the last four decades of research. Several keyword combinations were utilized, such as Tabernaemontana, indole alkaloids, cancer, cytotoxicity, antiproliferative, and multidrug resistance. Only peer-reviewed research articles or reviews were considered. Some books and official websites were also accessed. The literature was analysed by the authors, applying as exclusion criteria, poor quality, inaccurate data, and not considered relevant to the aim of the review. Mendeley Reference Manager Software (version 1.19.8, 2020) was used to manage the references and eliminate duplicates.
Indole alkaloids from Tabernaemontana genus with anti-cancer activity
Tabernaemontana bovina
T. bovina Lour. (synonym T. officinalis Tsiang) is indigenous to Southeast Asian, namely China, Cambodia, Laos, Myanmar, Thailand, and Vietnam. Its roots have been employed in Vietnam traditional medicine to treat fever and jaundice. The aspidosperma-type alkaloid 11-methoxytabersonine (1), (Fig. 4), isolated from T. bovina, significantly inhibited the viability of two human lung cancer cell lines A549 and H157 (IC50 values of 2.68 and 2.02 μM on A549 and H157 cells, respectively) (Ge et al. 2020). Similar results were reported by Liu et al. (2012) against a panel of cancer cell lines (Liu et al. 2012). Mechanistic investigations revealed that 1 induced autophagy, which conferred a cytoprotective effect, and concurrently triggered necroptosis rather than apoptosis in the two cell lines. Additionally, the authors have demonstrated that 1 induced autophagy in both cancer cells was caused by its effect on c-Jun N-terminal kinase (JNK) and AMP activated protein kinase (Ge et al. 2020). It is important to mention that this compound was firstly isolated from Melodinus aeneus (Baassou et al. 1978).
Several novel bisindole alkaloids of the vobasinyl-iboga type, including taberdivarines C–F (2–5, Fig. 4), were isolated from the leaves and twigs of the species. The cytotoxicity of taberdivarine C-F (2–5) against human cervical (HeLa), breast (MCF-7), and colorectal (SW480) cancer cell lines was evaluated by the thiazolyl blue tetrazolium bromide (MTT) metabolism assay. All the tested compounds (2–5) were found to be cytotoxic to the three tested tumour cell lines (IC50 values ranging from 1.42 to 11.35 μM), with taberdivarines E (4) exhibiting the greatest activity against HeLa and SW480 cancer cell lines, with IC50 values of 1.42 and 1.57 μM, respectively. Taberdivarine D (3) showed the highest cytotoxic effect on the MCF-7 cell line (IC50 value of 2.84 μM). All of the displayed activities were comparable to those of the positive control, cisplatin. (Zhang et al. 2015a).
The aspidosperma indole alkaloids jerantinines A (6) and D (7) were isolated from the leaves of T. bovina and screened for cells viability inhibition of three hepatoma SMMC-7721, HepG2 and Hep3B cell lines. Both compounds showed similar effects towards SMMC-7721, HepG2 cells with IC50 values of 1.66 and 1.33 µM for jerantinine A (6) and 1.17 and 1.47 µM for jerantinine D (7), respectively. In Hep3B cells, compound 7 proved to be the most active with an IC50 value of 1.85 µM versus 5.01 µM exhibited by compound 6. The activities displayed by both compounds were comparable to that of positive control vinorelbine (IC50 values of 3.02, 7.23, 0.60 towards SMMC-7721, HepG2 and Hep3B cells, respectively (Yu et al. 2023).
Tabernaemontana bufalina
Growing in the south of China, T. bufalina Lour. (syn. T. hainanensis (Tsiang) P.T.Li), which has previously received most of the research under the name Ervatamia hainanensis Tsiang, has been used in traditional Chinese medicine to treat snakebite, rheumatoid arthritis, hypertension, and viral hepatitis. According to phytochemical studies, T. bufalina is abundant in indole and bisindole alkaloids, having also diverse lanostane type triterpenes, lignans, and steroids. Among these, certain alkaloids showed notable anti-inflammatory, acetylcholinesterase (AChE) inhibitory and cytotoxic properties (Zhou et al. 2018; Xu et al. 2019). Several monoterpenoid indole alkaloids (8–25, Fig. 5), including three novel ones, were identified by Zhou et al. from the aerial parts of the plant: 3′-(2-oxopropyl)-19,20-dihydrotabernamine (8), 3′-(2-oxopropyl)-ervahanine B (9), and 19,20-dihydrovobparicine (10) (Zhou et al. 2018).The new compounds together with seven known ones (11, 14, 16, 17, 19, 22, and 23) showed cytotoxic activity against a human lung cancer (A-549) and a breast cancer (MCF-7) cell lines with IC50 values below 10 μM, being compound 16 the most active in both cell lines (IC50 1.25 µM and 1.19 µM, A-549 and MCF-7, respectively) (Table 1). The cytotoxicity evaluation of compounds was performed by using the sulforhodamine B (SRB) colorimetric assay, being 7-ethyl-10-hydroxy-camptothecin (SN38) used as a positive control (Zhou et al. 2018).
Conophylline (24), a bisindole alkaloid isolated from the same plant's branches and leaves, exhibited cytotoxic activity against the murine skin melanoma cell line B16 and the human breast cell line MDA-MB-231 cell lines (IC50 values of 0.13 and 8.9 μM, respectively) (Xu et al. 2019). The IC50 value on B16 cells was 68 times lower than that on MDA-MB-231 cells, revealing a significant level of selective cytotoxicity for the B16 cell line (Xu et al. 2019). Gambogic acid (IC50 values of 22.1 and 13.5 μM on B16 and MDA-MB-231 cells, respectively) was used by the authors as a positive control (Xu et al. 2019). Other indole alkaloids isolated, including the new undescribed monoterpenoid indole alkaloid (3R,7S,14R,19S,20R)-19-hydroxypseudovincadifformine (25), did not exhibit cytotoxic effect on the tested cells (IC50 > 100 μM)(Xu et al. 2019).
The phytochemical investigation on the aerial parts of T. bufalina led to the identification of the iboga-bobasine bisindole vobatensine C (26). When evaluated for its toxicity against A-549 human lung adenocarcinoma, Bel-7402 human hepatoma and HCT-116 human colon cancer cell lines, this compound showed significant bioactivity with IC50 values of 2.61, 1.19, and 1.74 μM, respectively (5-fluorouracil, with IC50 values of 0.80, 1.78 and 1.59 μM was used as control)(Chen et al. 2022).
Tabernaemontana catharinensis
T. catharinensis A. DC. is an arboreal species found in South America, namely Argentina, Paraguay, Bolivia, and Brazil. It is locally known as “corbina” and “forquilheira” in Rio Grande do Sul, Brazil. Traditionally, indigenous population uses this plant as an anticancer therapy. Beyond its anticancer activities, T. catharensis extracts have demonstrated antiparasitic, antiophidic, anti-inflammatory, anti-malarial, and anticholinesterase properties. These effects are attributed to the presence of indole alkaloids (Rosales et al. 2019; Reis et al. 2022).
From the stem bark of the plant four known alkaloids were isolated (Fig. 6, 27–30) (Reis et al. 2022). Their in vitro antiproliferative activity was screened on several tumour cell lines, showing affinisine (29) the best activity against all the cell lines tested, namely glioma (U251, GI50 9.5 µM), multidrug resistant ovarian adenocarcinoma (NCI-ADR/RES, GI50 8.3 µM), renal adenocarcinoma (786–0, GI50 8.3 µM), and colorectal adenocarcinoma (HT29, GI50 9.3 µM) cell lines (Table 2). Apopvincaminate (28) and voachalotine (30) were inactive in all cell lines, while voacangine (27) showed a moderate antiproliferative effect against the colorectal adenocarcinoma (HT29, GI50 14.4 µM) (Reis et al. 2022).
Tabernaemontana corymbosa
T. corymbosa (Roxb. ex Wall.) has a widespread distribution in the tropical and subtropical regions of Africa, America and Asia and possesses a vast application in traditional medicine.
Practically almost all parts of the plant, which include fruits, leaves, sap, latex, stem bark, root bark, and whole plant are employed as poultice, boiled juice, decoctions and infusions for treatment of several illnesses, including ulceration, fracture, postnatal recovery, syphilis, fever, orchitis and tumours in countries such as Malaysia, China, Thailand and Bangladesh (Abubakar and Loh 2016). Due to this reported pharmacological activities T. corymbosa has attracted interest among the scientific community, who have sought novel compounds to fight cancer. Among the array of compounds found in this plant, indole alkaloids have emerged as predominant and well-explored phytochemicals. However, it should be underscored that the geographic location and collection time can significantly influence the alkaloids profile of this plant (Lim et al. 2015). Furthermore, it is essential to acknowledge that T. corymbosa has been included on the International Union for Conservation of Nature list of threatened species (Smedley et al. 2018), which raises concerns about the sustainable supply of these promising metabolites.
As far as we know, the earliest report on indole alkaloids from T. corymbosa with potential in cancer treatment dates back to 1998, when Kam et al. (1998) isolated the dimeric vobasine-iboga bisindole conodiparines A–D (31–34, Fig. 7) from the plant leaves (Kam et al. 1998). All four compounds underwent screening to evaluate their capability in reversing multidrug resistance in vincristine-resistant human oral epidermoid KB cells. Results unveiled that while the compounds exhibited reduced toxicity against both sensitive (IC50 25.6–28.6 µM) and resistant (IC50 18.0–22.7 µM) KB cells individually, their concomitant treatment with 0.30 µM of vincristine (a concentration that did not affect the growth of the KB/VJ300 cells) substantially augmented their cytotoxic effects, leading to a IC 50 value of 1.9 µM for compound 31 (Kam et al. 1998). Although the mechanisms underlying this action remain undisclosed, the observed effect underscored the necessity for further exploration of conodiparines A–D (31–34), particularly concerning their potential as multidrug resistance reversal agents and whether the increased activity in combination with vincristine was attributed to an additive or synergistic effect.
Lirofoline A (35), a rare alkaloid characterized by a rearranged ibogan ring system, presented outcomes analogous to those observed with conodiparines (31–34). It exhibited diminished cytotoxicity against both drug-sensitive and vincristine-resistant KB cells. Notably, when co-administered with vincristine at a concentration of 0.12 µM, lirofoline A (35), effectively restored vincristine sensitivity in KB cells with vincristine resistance (VJ300) (Low et al. 2010).
The repertoire of alkaloid structures exhibiting drug resistance reversal properties was later expanded by the inclusion of the indole vincamajicine (36) and the vobasinyl-iboga bisindole alkaloids, ervatensines A (37) and B (38) isolated from the stem-bark (Lim et al. 2015). While vincamajicine (36) demonstrated drug resistance reversal activity solely in vincristine-resistant KB cells when used in combination with 0.12 µM vincristine (a concentration that did not affect the growth of the KB/VJ300 cells), ervatensines A (37) and B (38) displayed significant growth-inhibitory effects against both drug-sensitive (IC50 0.95–0.53 µM) and vincristine-resistant KB cells (IC50 0.98–1.11 µM) (Table 3). Unfortunately, reports detailing the underlying mechanism of this effect remain elusive. Moreover, compounds 37 and 38 exhibited robust growth-inhibitory activity against several human cancer cell lines (IC50 0.70–4.19 µM) (Table 4). Insights from cell cycle and annexin V-FITC apoptosis assays indicated that compounds 37 and 38 arrested proliferation in human colorectal carcinoma HCT-116 and estrogen-intensive human breast adenocarcinoma MDA-MB-468 cells, inducing apoptotic and necrotic cell death (Lim et al. 2015).
Some of the most intriguing compounds sourced from the plant leaves are the aspidosperma indole alkaloids, specifically jerantinines A–E (6, 39, 40, 7, 41, respectively). These compounds displayed pronounced cytotoxicity against both vincristine-sensitive (IC50 0.68–2.65 µM) and -resistant (IC50 0.95–2.03 µM) human KB cells, an unusual feature among simple aspidosperma alkaloids (Table 4). Furthermore, structural modifications, such as the acetylation of the free hydroxyl group in jerantinines A (6) and B (39) to yield derivatives 42 and 43, showed to be beneficial for the cytotoxicity, with IC50 values ranging from 0.70–1.04 μM (KB/S) and 0.75–83 μM (KB/VJ300) (Lim et al. 2008).
The exceptional properties of jerantinines swiftly attracted the interest of medicinal chemists. In that way, in 2013 Jérôme Waser et al. developed a method for the total synthesis of jerantinine E (41), involving 17 steps with a 16% overall yield. Subsequent in vitro assessments revealed that jerantinine E (41) displayed relevant cytotoxic effects on breast (MCF-7) and lung (A549 and HTB-178) cell lines, attaining IC50 values as low as 1 µM in A549 cells. Additionally, this compound was found to inhibit cell migration in all four cell lines, reducing it by 50–90% compared to untreated cells. Preliminary studies into its mechanism of action suggested that jerantinine E (41) disrupts the microtubule network, thus inhibiting tubulin polymerization (Frei et al. 2013).
The total synthesis of jerantinine A (6) was also developed (Smedley et al. 2018). Subsequent investigations led by Bradshaw and co-workers, entailed the evaluation of jerantinines A (6) and B (39) alongside their acetylated derivatives 42 and 43 towards additional cancer cell lines derived from colorectal (HCT-116, HT-29), breast (MCF-7, MDA-468) and lung (A549) carcinomas. Notably, these compounds consistently exhibited potent cytotoxic activities with IC50 values ranging from 0.26 to 3.74 µM. In general, compound 39 showed higher activity than 6 in the tested cell lines, suggesting that the epoxide moiety of 39 may confer enhanced potency. Interestingly, the acetate derivatives of jerantinines A (42) and B (43) possessed enhanced potency across most of the tested cell lines when compared to their parent compounds, specially compound 43, which depicted an IC50 lower than 1 µM in all cell lines (Raja et al. 2014). However, in clonogenic assays, a disparity emerged when the acetylated derivative 43 was compared with jerantinine B (39); jerantinine B acetate (43) showed reduced potency toward HCT-116 and MCF-7 after 24-h treatment period. These results suggested that the acetate derivative may act as a prodrug reliant on bioactivation by cellular esterases (Qazzaz et al. 2016).To shed some light on the mechanism of action, the authors focused on jerantinine A (6) for additional studies. This compound inhibited the HCT-116 and HT-29 cell colony formation and precipitated a profound cell cycle arrest at G2/M phase across all cell lines. Analogous to the action of jerantinine E (41), the cell cycle blockage by jerantidine A (6) was apparently related with the inhibition of tubulin polymerization. This inhibition perturbs the dynamic microtubule network, thereby preventing successful mitosis. The presence of aneuploidy and the downregulation of cyclin B1 supported these conclusions. In addition, the mode of action of this compound seemed to involve an apoptotic process of cell death subsequent to the cell cycle arrest (Raja et al. 2014). However, considering that the therapeutic potential of anti-microtubule and tubulin polymerization drugs such as vinblastine and paclitaxel is often constrained by phenomena such as drug resistance, toxicity and limitations in intravenous delivery, a similar output was anticipated for jerantinine A (6). Therefore, to overcome these limitations, Abubakar and co-workers envisioned a combination strategy. In this approach, jerantinine A (6) was concomitantly administered with γ-tocotrienol, a vitamin E isomer with pronounced in vitro anticancer activity (Abubakar et al. 2017). At low concentrations (3.14 µM for γ-tocotrienol and 0.42 µM for 6), this combination induced a potent antiproliferative effect on human glioblastoma (U87MG) cells. The combination index (CI) of 0.67 suggested a potential synergistic pharmacological effect (CI < 1). Treatment with these combined compounds also induced a G0/G1 cell cycle arrest, in contrast to the G2/M arrest observed when jerantinine A (6) was applied alone. On the other hand, both the combination and 6 alone led to the disruption of microtubule networks by triggering Fas- and p53-induced apoptosis, mediated via death receptor and mitochondrial pathways. The more relevant finding of this study was the observation of reduced undesirable toxicity to MRC5 non-tumoural fibroblasts when jerantinine A (6) and γ-tocotrienol were administered in combination. These outcomes underscore the therapeutic potential of this combination, achievable at lower individual doses, thereby mitigating the potential toxicity of jerantinine A (6) and surmounting the high-dose limitations of γ-tocotrienol (Abubakar et al. 2017). Furthermore, jerantinine A (6) also was found to induce tumour specific cell death in breast cancer cells by modulating splicing factor 3b subunit 1 (SF3B1), giving rise to abnormal splicing patterns that culminate in apoptosis (Chung et al. 2017). The precise mechanism by which jerantinine A (6) interferes with splicing activity remains to be elucidated. Nonetheless, these findings underscore jerantinine A's multi-targeted and tumour-specific nature, rendering it an appealing candidate for future development.
Jerantinine B (39) and its acetylated derivative (43) were also deeper explored by evaluating their activity against additional cancer cells, including MIA PaCa-2 (pancreatic) and vincristine resistant (VR) HCT-116 cells, as well as non-tumoural MRC5 fibroblasts. MIA PaCa-2 cells showed high sensitivity to both 39 and 43 with IC50 values of 0.25 μM. Interestingly, jerantinine B (39), as well as jerantinine A (6), exhibited activity against vincristine resistant HCT-116 cells expressing P-gp protein, featuring IC50 values of 0.44 and 0.49 respectively, which were lower than those observed for sensitive HCT-116 cells. Preliminary mechanistic studies unveiled that, in addition to the time- and dose-dependent induction of apoptosis, cell cycle arrest at G2/M phase and inhibition of tubulin polymerization, akin to analogues jerantinine A (6), jerantinine B (39) also triggered a substantial increase in the level of reactive oxygen species (ROS). This induction of ROS production may be correlated with the observed release of cytochrome c and caspase activation, preceding cellular apoptosis. Jerantinine B (39) was found to inhibit the activity of kinases involved in mitosis and significantly evoked potent G2/M cell cycle arrest with PLK1 being targeted in a dose-dependent manner (Qazzaz et al. 2016). Moreover, a synergistic pharmacological effect between jerantinine B (39) and δ-tocotrienol was observed in U87MG and HT-29 cells when both compounds were administered concomitantly, exhibiting CI values of 0.85 and 0.77 for U87MG and HT-29 cells, respectively. This resulted in up to a twofold and 3.8-fold dose reduction of δ-tocotrienol and jerantinine B (39), respectively (Abubakar et al. 2016). The anticancer effect of jerantinine B (39) was further validated towards acute myeloid leukaemia (AML), a heterogenous hematological malignancy with poor long-term survival. AML cell lines and patient samples exposed to jerantinine B (39) displayed significantly impaired cell growth in a dose-dependent manner, accompanied by an early-induced apoptotic cell death (occurring as early as 4 h after treatment). Studies on the mechanism of action suggested that effect of jerantinine B (39) in AML cells was associated with the induction of oxidative stress, particularly mitochondrial release of ROS, which subsequently triggered the activation of the c-Jun/JNK signalling pathway (Alhuthali et al. 2020). It is important to note that early activation of JNK has been reported as a specific mechanism mediating microtubule depolymerization and G2/M arrest (Chen et al. 2012). Finally, X-ray crystallography studies of the tubulin—(−)-jerantinine B acetate (43) complex demonstrated that this compound binds at the colchicine site resulting in microtubule disruption (Smedley et al. 2018). These collective findings underscore the potential of jerantinine B (39) and its acetylated derivative (43) to behave as potential multitarget anticancer agents (Table 5).
A series of 10 new indole alkaloids, tabercarpamines A − J, were isolated from the leaves of T. corymbosa. Within this set of compounds, only tabercarpamines A (44) and B (45) (Fig. 8), demonstrated noteworthy cytotoxic activities against human hepatocellular (SMMC-7721 and Hep-G2) and breast (MCF-7) carcinoma cell lines. Remarkably, compound 44 exhibited higher activity than cisplatin towards both hepatocellular cancer cell lines. Consequently, the authors extended their investigation into the anti-cancer properties of tabercarpamine A (44) in HepG2 cells to elucidate its mechanism of action, and the results revealed that the cytotoxicity might be related with its ability to induce apoptosis (Ma et al. 2014).
Four new vobasinyl-ibogan type bisindole alkaloids, tabercorines A–C (46–48) and 7-acetyl-tabernaecorymbosine A (49) (Fig. 8) were tested for their in vitro cytotoxicity against human leukaemia (HL-60), hepatocarcinoma (SMMC-7721), lung (A549), breast (MCF-7) and colorectal (SW480) cancer cell lines. No interesting inhibitory effects were observed for compound 48 (IC50 ranging from 14.95 to > 40 µM). Tabercorine B (47) on the other hand exhibited moderate cytotoxic activity (IC50 ranging from 4.70 to 16.93 µM), especially towards breast cancer cells (Zhang et al. 2015b). Subsequent studies further confirmed the anticancer potential of tabercorine B (47) with IC50 values ranging from 4.5 to 8.2 µM in several cell lines (Zhang et al. 2018b). However, the most compelling findings were associated with tabercorine A (46) and 7-acetyl-tabernaecorymbosine A (49), which displayed strong inhibitory properties (IC50 ranging from 2.98 to 9.24 µM for compound 46 and IC50 ranging from 2.90 to 4.75 µM to compound 49 comparable to those of the reference drug cisplatin (IC50 1.05–13.13 µM) (Zhang et al. 2015b) (Table 6).
Additionally, several other bisindole alkaloids demonstrated potent growth-inhibitory activities (IC50 < 10 μM) against an array of human cancer cell lines (Table 7). This group includes vobatensines A-E (50, 51, 26, 52 and 53, respectively) and the bisindoles 54–57 (Fig. 9), which were isolated from an ethanolic stem bark extract. The cell line with higher sensitivity for these compounds was HT-29, with IC50 values ranging from 0.92 to 7.2 µM. Nevertheless, none of the compounds displayed the ability to restore the sensitivity of vincristine-resistant KB cells to vincristine (Sim et al. 2016).
Conofolidine (58) and conophyllidine (59) (Fig. 9) were also isolated from ground leaf and steam bark ethanolic extract. Both of these compounds are aspidosperma dimers and belong to the bioactive conophylline group of bisindole alkaloids (Zhang et al. 2018a). While the structural elucidation of compound 58 was reported for the first time, conophyllidine (59) is known since 1993 (Kam et al. 1993). Remarkably, both conofolidine (58) and conophyllidine (59) showed pronounced growth inhibitory activities (IC50 ≤ 1.5 µM, Table 7) against human oral epidermoid carcinoma (KB/S), prostate carcinoma (PC-3 and LNCaP), breast adenocarcinoma (MDA-MB-231) and colorectal carcinoma (HT-29 and HCT 116) cancer cell lines (Nge et al. 2016). Furthermore, the growth inhibitory properties of conophyllidine (59) were later reinforced by other study, in which this compound showed potent cytotoxic activities, after a 48-h treatment against hepatic (Hep-G2, IC50 0.8 µM), lung (A540, IC50 1.15 µM) and gastric (SGC7901, IC50 0.87 µM) cancer cell lines. In addition, this compound apparently does not interact with tubulin or microtubules. Instead, it exhibited a robust inhibitory effect on the o Nf- kB signal pathway with an IC50 of 0.08 µM (Zhang et al. 2018a).
Tabercorymines A (60) and B (61) (Fig. 10) containing ibogan and vobasinyl units, represent a novel class of bisindole alkaloids that were isolated from the twigs and leaves of T. corymbosa. Compound 60 is of particular interest due to its unique heteropentacyclic ring system, resulting from the distinctive formation a C-7/C-20 bond in the vobasinyl unit. Both compounds showed moderate activity towards various human cancer cell lines. Compound 60 displayed a slightly higher activity profile (IC50 ranging from 4.8 to 12.9 µM) compared to 61 (IC50 ranging from 9.6 to 27.9 µM). However, it is worth noting that the dehydration of 60, leading to the formation of the C3-C14 unsaturated derivative, completely abolished its biological activity. This observation strongly suggested that the presence of the hydroxylated stereocenter at C-3 (vobasyl unit) plays a pivotal role in contributing to the antiproliferative activity of these alkaloids. Preliminary studies into the mechanism of action of compound 60, particularly in the context of MDA-MB-231 triple-negative breast cancer cells, showed that this compound induced cell cycle arrest at G2/M phase. Notably, unlike jerantinines A (6), B (39), and E (41), compound 60 did not appear to interfere with microtubule formation (Yuan et al. 2017).
The vobasinyl-ibogan-type bisindole alkaloids taburnaemines A–I (62–70), isolated from the twigs and leaves, have demonstrated significant antiproliferative activities, with exception of taburnaemine B (63). These activities were observed across various human cancer cell lines, including the P-glycoprotein-overexpressing multidrug-resistant KB cells. The IC50 values for these alkaloids ranged from 2.6 to 9.8 µM (Table 7). Alkaloids 62–67 are characterized by the presence of 1,3-oxazinane and 1,3-oxazolidine moieties in the vobasinyl and iboga units, respectively. However, the key structural determinant influencing the antiproliferative effects of these alkaloids appeared to be the absolute configuration of the 19,20-oxirane ring (Fig. 10). This conclusion was evident when comparing the activities of taburnaemine A (62) and taburnaemine B (63) (Table 7 and Fig. 10). The beta position of the 19,20-oxirane appeared to be an essential factor for the activity, as observed not only in taburnaemine A (62), C (64) and D (65), but also in tabercorymine B (61) (Zhang et al. 2018b).
Given the notable cytotoxic activities exhibited by bisindole alkaloids when compared to monomeric units, the search for novel molecules in this class was continuously prompted. This quest led to the discovery of four new aspidosperma − aspidosperma type alkaloids, the conolodinines A − D (71–74) (Fig. 11). When tested against a vast panel of human cancer cell lines, these compounds showed pronounced in vitro growth inhibitory activities with IC50 values falling in the 0.01–5 μM range. However, only low activities were obtained against vincristine-resistant KB and lung cancer (A549) cells (IC50 > 10 μM). Notability, when administered along with vincristine, conolodinines A − D (71–74) proved to be able to restore the sensitivity of KB/VJ300 cells to the anticancer drug (Table 7) (Sim et al. 2019).
The aspidosperma-aspidosperma taberyuine A – C (75–77), and the ivobasinyl-ibogan bisindoles taberyuines H (78) and I (79) (Fig. 12) were also tested for their antiproliferative activities. Taberyuines A (75) and C (77), H (78) and I (79) showed only moderated activity, with IC50 values ranging between 2.4 and 16.8 µM, when assessed in human liver (HepG2), lung (A549) and gastric (SGC7901) cancer cell lines after 48-h exposure (Table 8). In contrast, taberyuine B (76) presented stronger cytotoxic properties, with IC50 values raging between 0.7 and 2.1 µM. According to these results, it became evident that the 14′,15′-epoxy moiety has a detrimental effect on cytotoxic activity. Conversely, the presence of the furan ring in structures 75–77 appeared to be crucial for activity, as several other taberyuines (D, E, F, and G), lacking this moiety, exhibited no activity against the tested cell lines. The transcription factor NF-κB lays a pivotal role in the regulation of immune and inflammatory responses, which are frequently involved in pathogenesis and treatment of cancers. Preliminary studies suggested that the mode of action of taberyuine B (76) involves the inhibition of the NF-kB signal pathway (IC50 0.18 µM) (Zhang et al. 2018a).
It is well-established that targeting autophagy in cancer treatment holds promise as a therapeutic strategy, but it also represents a double-edge sword effect. On one hand, autophagy suppresses tumourigenesis by limiting the production of reactive oxygen species and DNA damage. However, it subsequently adapts to support the survival of cancer cells and fosters the tumourigenicity of cancer stem cells at established sites. Consequently, the intricate autophagic process, governed by an array of proteins, emerges as an appealing target for cancer therapy. Thus, the use of autophagy modulators as adjuvant therapy has been explored by researchers (Lim et al. 2021). In this context, Xiao-Jiang Hao explored the potential of a series of monoterpenoid indole alkaloids sourced from T. corymbosa to modulate autophagy. Compounds such as taberine D (80), tabernaelegantine B (81), conodurine (82) and tabernaricatine C (83) (Fig. 13) demonstrated the ability to disrupt the autophagic flux. This effect appears to be associated with the attenuation of lysosomal acidification, thereby impeding the fusion of autophagosomes and lysosomes. In addition, compounds 80 and 83 also exhibited cytotoxic potency on par with that of cisplatin across various human cancer cell lines. These cumulative observations unveil new molecular mechanism underlying anti-cancer effects of these indole alkaloid compounds (Zhang et al. 2020).
Tabernaemontana divaricata
T. divaricata (L.) R. Br. ex Roem. & Schult (syn. Ervatamia divaricata) is an evergreen shrub or small tree, commonly known as Crepe Jasmine. The species is widely distributed in Asia, Australia, mangrove forest of China, Japan and India, being also cultivated as ornamental plant due to its shiny deep green leaves and white colored fragrant flowers (Ghosh et al. 2021). Various parts of T. divaricata have been extensively used in Ayurvedic, Chinese and Thai traditional medicines for the treatment of a several human ailments due to the antioxidant, anti-tumour, and analgesic properties. It is used to treat fever, headache, dysentery, vomiting and diarrhea, abdominal tumours, inflammation, leprosy, and asthma. Additionally, it is also used as anthelminthic, antihypertensive, and as tonic for brain, liver, and spleen (Pratchayasakul et al. 2008; Bhadane et al. 2018; Ghosh et al. 2021).
Taberdivarines A–B (84–85) were isolated from the leaves of the plant, being the first aspidosperma–aspidosperma-aspidosperma alkaloid trimers with a furan ring linkage (Chen et al. 2021). Moreover, six new dimers named taberdivarines C–HFootnote 1 (86–91) were also reported (Fig. 14). The cytotoxicity of taberdivarines A–H (84–91) was evaluated against three human cancer cell lines, SMMC-7721 (hepatocellular carcinoma), HT-29 (colorectal adenocarcinoma) and A549 (non-small cell lung) by the MTS assay (Table 9). Taberdivarine F (89) was the most cytotoxic compound against the three cell lines, displaying IC50 values of 0.30 (SMMC-7721), 0.75 (HT-29) and 3.41 (A549) μM, comparable to those obtained for the positive control vinolrebine (IC50 values of 3.02, 0.14 and 2.23 μM, respectively). Compounds 90 and 91 were also very active against SMMC-7721 cells (IC50 values of 1.72 and 2.01 μM), and HT-29 and A549 carcinoma cells (IC50 values ranging from 4.05 to 9.73 μM). Similar IC50 values were obtained for taberdivarine A (84) on all cell lines tested, while taberdivarines C (86) and D (87) showed a moderate cytotoxic activity against SMMC-7721 and HT-29 cancer cells but were non cytotoxic on A549 cell line (IC50 > 40 μM). Compounds 85 and 88 showed no cytotoxicity (Chen et al. 2021).
Zhang et al. isolated five new vobasinyl−ibogan-type bisindole alkaloids, tabernaricatines A−E (83, 92–95), and two new monomers, tabernaricatines F and G (96 and 97) from the aerial parts of T. divaricata (Fig. 15) (Zhang et al. 2013). Several known indole alkaloids, including ervachinine A–C (98–100), cononitarine B (101), conofoline (102) (Fig. 16) and conophylline (24) (Fig. 5) were also isolated. Tabernaricatines A (92) and B (93) were the first examples of alkaloids possessing a vobasine–iboga scaffold with a six-membered ring formed by an ether linkage between C-17 and C-21 in the vobasine unit. Excepting for compound 83, all the isolated alkaloids were assayed for their cytotoxicity against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Compounds 93 and 94–96 were found to be non-cytotoxic (IC50 > 40 μM). Among the cytotoxic compounds it was interesting to observe a higher activity against the human myeloid leukaemia (HL-60) cell line (IC50 0.17–3.88 μM) when comparing with the other cancer cell lines (Table 9). Particularly, conophylline (24) showed the strongest activity against all the cell lines tested, (IC50 values ranging from 0.17 to 1.49 μM), being even more cytotoxic than cisplatin (IC50 between 1.14 and 16.84 μM), used as positive control. Tabernaricatine A (92) also exhibited significant inhibitory effects on HL-60 (0.79 μM), SMMC-7721 (3.41 μM), A-549 (3.52 μM), MCF-7 (3.10 μM), and SW480 (2.59 μM). Tabernaricatine G (97), ervachinines A-C (98–100), and conofoline (102) displayed moderate cytotoxicity against A-549, MCF-7 and SW480 cell lines (IC50 10.35–28.53 μM) (Zhang et al. 2013).
From the stems of the plant, several alkaloids were isolated, including the new monoterpenoid bisindole compounds flabellipparicine (103), 19,20-dihydrovobparicineFootnote 2 (104), 10′- demethoxy-19,20-dihydrovobatensine D (105), and 3′-(2-oxopropyl)ervahanine A (106). Deoxytubulosine (112), a β-carbolinebenzoquinolizidine alkaloid was also obtained (Fig. 17) (Cai et al. 2018). Flabellipparicine (103) features an uncommon flabelliformide-apparicine-type scaffold linked with a C-3 − C-22′, and a N-1 − C-16′ bonds giving rise to the five-membered ring between the two monomers. All compounds were screened for their cytotoxic activity against human breast (MCF-7) and human lung (A-549) cancer cell lines, using 7-ethyl-10-hydroxy-camptothecin (SN38) as positive control (IC50 values of 0.1 and 0.2 nM, respectively) (Table 10). Deoxytubulosine (112) was significantly cytotoxic displaying IC50 values of 2 and 90 nM, respectively. Among the bisindole alkaloids set, the most active compounds were those possessing two indole NH groups (104, 106–109 and 4), which showed IC50 values ranging from 0.8 μM (104) to 7.3 (108) μM on MCF-7 cell line, 1.2 μM (106) and 8.1 μM (104) on A-549 cell line. On the other hand, alkaloids 103 and 105, having only one indole NH group showed IC50 values higher than 10 μM on MCF-7 and A-549 cell lines, respectively (Cai et al. 2018).
Two unique vobasine-iboga-vobasine-type alkaloids, ervadivamines A (113) and B (114) were also isolated from the roots ethanolic extract (Liu et al. 2018). These trimers were the first alkaloids containing two different types of constitutional units, linked through C-3−C-11′ and N-1′−C-3′′ bonds, respectively (Fig. 18). Interestingly, the dimeric (19,20-dihydroervahanine A, 115) and monomeric (bogamine and ibogaine) precursors were also isolated, which allowed the proposal of a biogenetic pathway. Compound 115 exhibited significant cytotoxic activity against HT-29 (IC50 3.44 μM) and A549 (IC50 8.74 μM), displaying higher IC50 values against MCF-7 and HepG2/ADM (hepatocellular carcinoma adriamycin-selected multidrug resistant) cell lines (19.49 and 16.63 μM, respectively). Among the new isolated trimers, ervadivamine A (113) was cytotoxic against all cancer cell lines (IC50 ranging from 10.25 to 12.55 μM), including the adriamycin-resistant HepG2 cell line. Curiously, ervadivamine B (114) that differs from ervadivamine A (113) by having an additional methoxy group at C-10′ (ibogain moiety) was inactive against the MCF-7 and HepG2/ADM cell lines (IC50 > 50 μM) (Liu et al. 2018).
Lirofolines A (35) and B (116) are pentacyclic indole alkaloids having a new rearranged ibogan ring, isolated from T. corymbosa and T. divaricata, respectively (Low et al. 2010). Despite being non-cytotoxic against both drug-sensitive and vincristine-resistant KB cells, both alkaloids demonstrated multidrug resistance reversing effect in vincristine-resistant KB cells with IC50 of 10.5 and 21.2 μM, respectively, in the presence of 0.12 μM of vincristine (Low et al. 2010).
Tabernaemontana elegans
T. elegans Stapf. is a shrub or small tree found in East and Southeastern Africa, including Mozambique. It is used in African traditional medicine for treating several diseases. The powdered root bark or fruits have been used to treat cancer. Decoction of root has been used for washing wounds and to treat pulmonary diseases, while maceration of root ash is drunk to treat tuberculosis. The use of roots, stem bark and seeds for treating heart diseases is also reported (PROTA Foundation 2008).
Aiming at obtaining new plant-derived anticancer compounds with emphasis on targeting multidrug resistance in cancer, our research group has been carrying out the phytochemical study of the alkaloid fractions of the methanol extracts of leaves and roots of T. elegans, which allowed the isolation of several indole alkaloids, including β-carbolines, and monoterpene indole alkaloids of the corynanthe-type. Several bisindole alkaloids of the vobasinyl-iboga-type were also isolated (Ferreira and Paterna 2019). As reviewed, aiming at generating a library of new compounds sharing the monoterpene indole alkaloid scaffold, tabernaemontanine (117) and dregamine (118), two major epimers found in T. elegans with a monoterpene indole alkaloid scaffold of the corynanthe-type, were derivatized through condensation of the ketone group with different amine derivatives, to yield several compounds with new nitrogen-containing aromatic and aliphatic moieties. Condensation of tabernaemontanine (117) and dregamine (118) with hydrazine hydrate and further reaction with different aldehydes yielded azines. Acyl derivatives were also prepared after reduction of compounds 117 and 118 (Fig. 19) (Ferreira and Paterna 2019).
As detailed previously (Ferreira and Paterna 2019), some of the referred natural indole and bisindole alkaloids were able to induce apoptosis and to arrest cell cycle, whereas the derivatives were found to be P-gp and MRP1 inhibitors in resistant cancer cells, overexpressing these ABC transporters. Compounds with selective toxicity against resistant cancer cells overexpressing MRP1 were also reported. It was concluded that the introduction of aromatic nitrogen-containing moieties at the carbonyl group of the indole alkaloid scaffold of tabernaemontanine (117) and dregamine (118) increased significantly the capacity of some compounds as P-gp inhibitors when compared with the starting natural compounds (Ferreira and Paterna 2019).
Consequently, based on the previous encouraging results and aiming at increasing the number of analogous for structure–activity relationship studies, a new set of N-alkylated derivatives was prepared through reaction of the indole nitrogen of compounds 117 and 118, with different aliphatic and aromatic halides, yielding twenty-six new N-alkylated derivatives (Fig. 19) (Cardoso et al. 2021a).
Likewise, and aiming mostly to obtain new derivatives containing new nitrogen atoms and aromatic rings, two new set of compounds were also prepared by condensation of the carbonyl at C-3 of dregamine (118) with hydrazine followed by reaction with different aldehydes, to obtain nineteen new azines (145–163) (Fig. 20), whereas the reaction of with isocyanates yielded eleven new semicarbazones (164–174) (Fig. 21)(Cardoso et al. 2021b).
MDR reversal activity
All N-alkylated (119–144), azine (145–163) and semicarbazone (164–174) derivatives were evaluated for their MDR reversal ability, by functional and chemosensitivity assays, using as model resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells, overexpressing P-glycoprotein. In the functional assay, the capability of compounds was measured by determining fluorescence activity ratio (FAR) values, measuring the cytoplasmic accumulation of rhodamine-123, by flow cytometry. Verapamil, a known P-gp inhibitor, was used as positive control (Cardoso et al. 2021a, b).
When comparing with the starting compounds, which were practically inactive (117 and 118), an important increase of activity was found for most of the derivatives. In the set of N-alkylated derivatives (119–144), which were not cytotoxic or showed weak cytotoxicity, the most active compounds in the transport assay, were those sharing N-phenethyl moieties (141–144), with bromo or methoxy substituents, displaying remarkable P-gp inhibitory activity. At the lowest concentration (2 μM), compound 143, which was not cytotoxic, was the strongest P-gp inhibitor (Table 11), exhibiting more than 20-fold higher activity than the positive control, verapamil, at 20 µM. Strong activity was also found for compounds containing a N-benzyl substituted with a halogen atom (125–128 and 134) (Table 11). Most of dregamine derivatives were stronger P-gp inhibitors than the corresponding derivatives of tabernaemontanine (117) suggesting that the stereochemistry at C-20 might be import for the activity. The MDR reversal activity of this set of derivatives was corroborated in chemosensitivity assays, exhibiting most of the derivatives tested very strong synergism with doxorubicin (combination index, CI < 0.1), being the most effective compounds 143 and 144.
In QSAR models, which were generated for having further insights on the structural features important for effective drug-receptor interactions, it was concluded that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.
Similarly, significant MDR reversal activity was observed for dregamine azine (145–163) and semicarbazone (134–174) derivatives (Figs. 20 and 21). When comparing the antiproliferative activity with that of the starting compound 118 (IC50 37.21 µM, sensitive cells; 22.97 µM, resistant cells), conversely to N-alkylated analogous, most of the derivatives showed higher antiproliferative activity against both sensitive L5178Y mouse T-lymphoma cells (PAR) and resistant human ABCB1-gene transfected L5178Y subline (MDR) (IC50 values ranging from 5.43 to 26.40 µM, sensitive cells; 4.28 to 12.91 µM, resistant cells). Moreover, most of the compounds showed selectivity against the MDR cells (relative resistance, RR < 1) exhibiting compounds 147, 149, 151, 153, 155, 156, 165, 166, collateral sensitivity effect (RR ≤ 0.5). The MDR-selective properties of these compounds, in P-gp-overexpressing cells, might be explained, at least partially, by their possible metal-chelating properties (Heffeter et al. 2019) (Table 12).
When comparing with dregamine (118), an important increase of P-gp inhibitory activity was also observed for most of these compounds, mainly those containing an azine moiety with aromatic substituents, being compounds with trimethoxy-phenyl (159), or naphthyl motifs (160 and 161) the strongest P-gp inhibitors at the lowest concentration (0.2 µM; FAR > 10; Table 13). At 2 µM, a remarkable inhibition of P-gp efflux activity was found for most of the azines with aromatic moieties, being the strongest inhibitors compounds 158–163 (FAR > 95.5). On the contrary, no significant activity was found for the azine derivative with an aliphatic moiety (145). Conversely to azines, the semicarbazone derivatives of dregamine (164–174) exhibited significant activity only at the highest concentration tested (2 µM), being more active also those compounds bearing aromatic moieties (167–174) (FAR values of 3.20–8.77 at 2 µM).
The results obtained for these derivatives corroborated the importance of the introduction of new aromatic moieties to the indole alkaloid scaffold for enhancing the activity by generating extra electrostatic and π-π interactions with the amino acid residues with P-gp. The role of H-bonding acceptor potential of P-gp inhibition was also evidenced in this study.
In drug combination assays, most of the compounds of both sets synergized doxorubicin in the same cell lines, substantiating their potential as MDR reversers. Selected azine and semicarbazone derivatives (154, 159, 160, 162 and 171) were found to behave as inhibitors in the ATPase activity assay. Likewise in the set of N-alkylated derivatives, in generated QSAR models, it was deduced that lipophilicity and bulkiness features of compounds were related with higher P-gp inhibitory activity.
Homologous DNA repair inhibitors
The treatment of triple-negative breast and advanced ovarian cancer remains a great challenge, relying mostly on platinum drugs and currently on Poly (ADP-ribose) polymerase (PARP) inhibitors, such olaparib, which are in the frontline for the treating of breast and ovarian cancer with BRCA-deficient tumours. However, despite PARP inhibitors success, resistance to these agents has been reported, limiting their clinical use. Therefore, therapeutic alternatives, for sensitizing cancer cells to the effect of PARP inhibitors and other anticancer agents, are very important in cancer therapy. Recently, we have identified a dregamine hydrazone derivative (175, Fig. 22) that targeted homologous recombination DNA repair defects, by disrupting BRCA1-BARD1 heterodimer complex, in triple-negative breast and ovarian cancers (Raimundo et al. 2021) To evaluate its antitumour activity and molecular mechanism of action, two- and three-dimensional cell cultures with different BRCA1 status, as well as patient-derived cell lines and xenograft mice models were used.
BBIT20 (175) was highly effective, mostly against triple-negative breast cancer cells (IC50 values ranging from 4 to 6 μM in BRCA1-deficient cancer cells) when compared to cisplatin and the targeted drug olaparib, which showed much higher IC50 values. Moreover, BBIT20 (175) showed selectivity to cancer cells displaying much lower antiproliferative effect in non-malignant cells (IC50 values ≅ 30). In xenograft mouse models of ovarian cancer cells, by intraperitoneal administration, BBIT20 (175) displayed strong antitumour activity at very low concentration (2 mg kg−1), being much more active than olaparib at 50 mg.kg−1. Throughout the experiment, mice have not shown significant morbidity signs or alteration of body weight. In combination assays, BBIT20 (175) sensitized triple-negative breast and ovarian cancer cells to the effect of cisplatin and olaparib. Its synergy with these anticancer drugs was related to apoptosis induction.
Moreover, triple-negative breast and ovarian cancer cells did not develop resistance to BBIT20 (175) when exposed to several rounds of selection with increasing concentrations. Interestingly, BBIT20 (175) was previously found to be a strong P-gp inhibitor in resistant human ABCB1-gene transfected L5178Y mouse T-lymphoma cells (FAR 55.9 at 2 µM) (Paterna et al. 2017), thus corroborating its great potential for reversing drug-resistance. It was the first disrupter of BRCA1-BARD1 complex reported. As a single agent or in combination with anticancer drugs, namely PARP inhibitors, BBIT20 (175) is a promising lead for treating aggressive and resistant cancers, particularly triple-negative breast, and advanced ovarian cancer.
Other Tabernaemontana species
Tabernaemontana arborea
T. arborea ROSE ex J.D.SM., a shrub or small tree native to the tropical rainforests of Mexico, Central America, and Colombia, is used in Mexican traditional medicine due to their analgesic, anti-inflammatory, and dermatological properties (González-Trujano et al. 2023).
A bioassay-guided fractionation of the sap of this plant resulted in isolation of the known monoterpene indole alkaloid voacangine (27) (Fig. 6), along with the bisindole alkaloids voacamine (176) and epivoacorine (177) (Fig. 23). The cytotoxic activity of the three alkaloids was evaluated, and the half dose effect (ED50) values in the P-388 lymphocytic leukaemia cells were 18.5 (27), 3.7 (176) and 2.4 (177) µM (Kingston 1978).
Tabernaemontana calcarea
T. calcarea Pichon, also known as Pandaca calcarea, is a forest understory shrub predominantly found in the western and northern regions of Madagascar. Three new indole alkaloids, 19-epi-3-oxovoacristine (178), 19-epi-coacristine hydroxyindoleine (179), and 3R/S-hydroxytabernanthine (180), along with the previously known indole alkaloids voacangine (27), isovoacangine (181), coronaridine (182), 11-hydroxycoronaridine (183), voacristine (184), 19-epi-voacristine (185), isovoacristine (186), ibogamine (187), 10-methoxyibogamine (188),heyneanine (189) and 19-epi-heyneanine (190) (Fig. 24), were isolated using a bioassay-guided fractionation. They were found to be marginally cytotoxic to ovarian cancer cells A2780, with IC50 values ranging from 12.5 to 28.6 µM (Chaturvedula et al. 2003).
Tabernaemontana inconspicua
T. inconspicua Stapf., a shrub known for its green to yellow or orange bark, is native to Africa and widely distributed across various tropical countries. This species has received little research attention, and only a few studies have indicated the presence of indole alkaloids exhibiting cytotoxic effects (Ngah et al. 2022).
5,6-Dioxo-11-hydroxyvoacangine (191) (Fig. 25) inhibited the cell growth of human breast cancer MDA-MB-231 cells, with IC50 values after 24 h and 48 h of treatment of 3.35 and 2.19 µM, respectively (Laura et al. 2021).
Tabernaemontana pachysiphon
T. pachysiphon Stapf. is a perennial broad-leaved tree reaching up to 15 m and found in the coastal tropical lowland forests of East Africa. Root cortex decoctions are widely used in traditional African medicine, as they are believed to contain medicinal properties. Notably, T. pachysiphon is characterized by the presence of monoterpene indole alkaloids in all its parts (Höft et al. 1998). Phytochemical investigation of the leaves led to the isolation of 21 new bisindole alkaloids of the aspidosperma—aspidosperma type, including the new tabernaesines A − J (192–200), and the known 2′-hydroxyvoafoline (201) and isovoafolidine (202) (Fig. 26). Their cytotoxic activity was assessedon human cancer cell lines from, skin (SK-MEL-28), colon (SW480), liver (HepG2), breast (T47D and MDA-MB-231) and lung (A549), through the thiazolyl blue tetrazolium bromide assay. Tabernaesines A (192) and F (197), and 2′-hydroxyvoafoline (201) exhibited significant inhibitory effects on SK-MEL-28, SW480, HepG2, and T47D with IC50 values ranging from 2.5 to 9.8 μM. Tabernaesines E (196) and G (198) were also cytotoxic against some cancer cell lines (IC50 values ranging from 7.4 to 9.5 μM). Moreover, isovoafolidine (202) exhibited cytotoxicity to MDA-MB-231 cells (IC50 of 8.3 μM) (Yi et al. 2020).
Tabernaemontana sphaerocarpa
T. sphaerocarpa Blume is a small tree native to Indonesia and it is found mostly in Java. This species has several traditional uses, including the leaves used as a laxative, the flowers as a cardiotonic agent, and the latex has been applied for wart removal. Fractionation of the dichloromethane-soluble fraction of the methanol extract of T. sphaerocarpa stems gave rise to the isolation of two new bisindole alkaloids, biscarpamontamines A (203) and biscarpamontamine B (204), together with vobtusine (205), vobtusine lactone (206), and 3-hydroxyvobtusine (207) bisindole alkaloids (Fig. 27), which were evaluated for their cytotoxic activity against the human leukaemia (HL60), multiple myeloma (RPMI8226), lung cancer (NCI-H226), colon cancer (HCT116), and breast cancer (MCF7) cells. Among them, biscarpamontamine B (204), and 3-hydroxyvobtusine (207) exhibited the most significant cytotoxic effect with IC50 values ranging from 0.5 to 2.4 μM and 0.8–2.4 μM, respectively (Zaima et al. 2009).
Conclusions and future perspectives
Tabernaemontana species have long been used in traditional medicine to treat various diseases, including tumours. Their strong biological activity has been attributed mostly to the indole moiety of monoterpene indole and bisindole alkaloids. In fact, due to its chemical characteristics and biological properties, the indole nucleus has been considered a privileged scaffold in the development of anticancer drugs. It is found not only in plant-derived indole alkaloids in clinical use, such as vinblastine and vincristine, but also in several synthetic anticancer drugs. Thus, in the quest for new anticancer indole alkaloids, several researchers have been carrying out the phytochemical study of Tabernaemontana species.
The main objective of this review was to summarize these studies and to highlight our own contribution related to the study of Tabernaemontana elegans. A high number of monoterpene indole and alkaloids has been isolated and evaluated for their anticancer potential. Many compounds showed encouraging in vitro activity against sensitive and resistant phenotypes, through modulation of various signalling pathways, namely inhibition of cancer cell proliferation, cell cycle arrest, and apoptosis induction. The ability of monoterpene indole alkaloid derivatives, obtained by simple modifications of functional groups, to reverse multidrug resistance mediated by ABC transporters, mostly P-gp, has also been well documented by our group. The remarkable in vitro and in vivo results showed by the dregamine derivative BBIT20 (175), in triple-negative breast and ovarian cancers, strongly highlighted the importance of monoterpene indole alkaloids as leads in drug development. It revealed great potential for treating aggressive and resistant cancers directly or in combination with anticancer drugs currently in the frontline of BRCA-deficient tumours treatment.
Although a great number of studies has been reporting the anticancer properties of monoterpene indole alkaloids, in most cases the underlying mechanisms are often unclear or unexplored and should be thoroughly investigated. In addition to in vitro tests, in vivo studies should also be performed. They represent complex models that can address several issues that are not achievable through in vitro studies, namely, to evaluate the safety, toxicity, and efficacy of a lead compound and thus, together with in vitro studies provide a holistic understanding of the pharmacodynamic and pharmacokinetic profiles of lead compounds.
Data availability
Not applicable.
Notes
This name is used by other authors to name compounds with different structures.
This name is also used to name other compound with a different structure.
Abbreviations
- ABCB1 :
-
ATP binding cassette, subfamily B, member 1
- BARD1 :
-
BRCA1-associated ring domain protein
- BRCA1 :
-
Breast cancer type 1 susceptibility protein
- FAR :
-
Fluorescence activity ratio
- IC 50 :
-
Sample concentration causing 50% inhibition
- JNK :
-
C-Jun N-terminal kinase
- MDR :
-
Multidrug resistance
- MTT :
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PARP :
-
Poly (ADP-ribose) polymerase
- P-gp :
-
P-glycoprotein
- ROS :
-
Reactive oxygen species
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The authors thank Fundação para a Ciência e a Tecnologia (FCT), Portugal, for financial support through the project 2022.05718.PTDC and PhD fellowship 2020.06020.BD (Filipa Barbosa).
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Gonçalves, B.M.F., Duarte, N., Ramalhete, C. et al. Monoterpene indole alkaloids with anticancer activity from Tabernaemontana species. Phytochem Rev (2024). https://doi.org/10.1007/s11101-024-09964-6
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DOI: https://doi.org/10.1007/s11101-024-09964-6