Synthesis and biological evaluation of novel N⁹-heterobivalent β-carbolines as angiogenesis inhibitors

Abstract

A series of novel N9-heterobivalent β-carbolines has been synthesized. All the novel compounds were tested for their anticancer activity against six tumour cell lines in vitro. Among these molecules, compounds 5b, and 5w exhibited strong cytotoxic activities with IC50 value of lower than 20 μM. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 5b and 5w exhibited that tumour inhibition rate of over 40% in the Sarcoma 180 and Lewis lung cancer animal models. Preliminary structure–activity relationships (SARs) analysis indicated that: (1) C1-methylation and C7-methoxylation were favorable for increased activities; (2) 3-Pyridyl or 2-thienyl group substituent into position-1 of the β-carboline core, and the aryl substituent into another β-carboline ring might be detrimental to cytotoxic effects of this class compounds. Investigation of the preliminary mechanism of action demonstrated that compound 5b had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay.

Recent Insights into β-Carboline Alkaloids with Anticancer Potential

“…Dai et al [98] have reported compound 10 and 11 a novel N 9 heterobivalent β-carbolines (Figure 9) with an IC 50 value 8.4 and 14.1µM respectively against MCF-7 cell line. In vivo studies were performed for the compound 10 and 11 against mice, with tumor inhibition rate 40% bearing Sarcoma 180 and Lewis lung cancer.…”

Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

“…So our group reported the synthesis, in vitro evaluation, in vivo efficacies, and SARs of the new homobivalent β-carbolines and heterobivalent β-carbolines with alkyl or alkylamino spacers in positions 1, 3, 7, and 9 of the β-carboline nucleus (Figure 2) [39,40,41,42]. In these homobivalent β-carbolines, 1-Methyl-9-[4-(1-methyl-β-carboline-9-yl)butyl]-β-carboline (B-9-3) [43,44] exhibited potent antitumor activity.…”

A new potential anti‐cancer beta‐carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

“…Despite its antitumor potential, the neurotoxicity caused by harmine in vivo limited its development for therapeutic uses (Cao et al, ; Chen et al, ). Thus, other harmine derivatives with different number of substituents were synthetized and tested for their antitumor potential in vitro and in vivo displaying lower toxicity than harmine and interfering with different cancer cell processes, such as cell cycle, apoptosis, angiogenesis, and production of ROS (Cao et al, ; Guo et al, ; Han et al, ; Li et al, ; Luo et al, ; Ma, Chen, & Chen, ; Zhang et al, ; Zhang et al, ). In that context, the previously synthesized harmine derivative CM16 (Figure a) (Meinguet et al, ) has been shown to display in vitro antiproliferative activity on various cell types including glioma models via, at least partly, an alteration of the initiation phase of protein translation (Carvalho et al, ).…”