Abstract
Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.
Highlights
Microtubule-binding agents have been developed as an effective therapy in cancer treatment due to the key roles of microtubules in cell proliferation, signal transduction, and cell migration [1]
In cells treated with alkaloids 3, 4, 6, 7, and 13, dotted tubulin aggregations without spindles were seen in the phosphorylated histone H3 (pH3)-positive mitotic cells, while microtubules were undetectable in pH3-negative interphase cells (Figure 2B)
All isolates were evaluated for antiproliferative activity against five human tumor cell lines, including the multidrug resistance (MDR) subline KB-VIN
Summary
Microtubule-binding agents have been developed as an effective therapy in cancer treatment due to the key roles of microtubules in cell proliferation, signal transduction, and cell migration [1]. Overexpression of P-glycoprotein encoded by thedrugs, ABCB1 gene leads to poor disease prognosis, disease prognosis, and most clinical antimicrotubule including paclitaxel (PXL), vincristine and most clinical antimicrotubule including paclitaxel (PXL), B,. The vinca alkaloids exhibit significant anticancer activity family [6]. The vinca alkaloids exhibit significant anticancer activity and and vincristine, vinblastine, vinorelbine, vindesine, and vinflunine have approved been approved for clinical vincristine, vinblastine, vinorelbine, vindesine, and vinflunine have been for clinical use in use the treatment of hematological and lymphatic neoplasms [7]. In prior biological activity activity studies, studies, several several aspidosperma-type MIAs, such as jerantinines A, B, and E from T. corymbose, displayed displayed significant significant antiproliferative antiproliferative activity against cancer cancer cells cells [8].
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