Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

Abstract

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic spacer in the natural leads by a more flexible hydrazide linker while sparing the two peripheral indole rings. All the synthesized bis-indoles were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. The most potent congeners 7e and 9a against MCF-7 cells (IC50 = 0.44 ± 0.01 and 1.28 ± 0.04 μM, respectively) induced apoptosis in MCF-7 cells (23.7-, and 16.8-fold increase in the total apoptosis percentage) as evident by the externalization of plasma membrane phosphatidylserine detected by Annexin V-FITC/PI assay. This evidence was supported by the Bax/Bcl-2 ratio augmentation (18.65- and 11.1-fold compared to control) with a concomitant increase in the level of caspase-3 (11.7- and 9.5-fold) and p53 (15.4- and 11.75-fold). Both compounds arrested the cell cycle mainly in the G2/M phase. Furthermore, 7e and 9a displayed good selectivity toward tumor cells (S.I. = 38.7 and 18.3), upon testing of their cytotoxicity toward non-tumorigenic breast MCF-10A cells. Finally, compounds 7a, 7b, 7d, 7e, and 9a were examined for their plausible CDK2 inhibitory action. The obtained results (% inhibition range: 16%–58%) unveiled incompetence of the target bis-indoles to inhibit CDK2 significantly. Collectively, these results suggested that herein reported bis-indoles are good lead compounds for further optimization and development as potential efficient anti-breast cancer drugs.

Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights

“…The utilised procedures in the biological assays were performed as described earlier; cytotoxicity 47 , cell cycle 48 , Annexin V-FITC Apoptosis 49 and CDK2 50 assays, whereas all detailed procedures were mentioned in the Supplementary Materials .…”

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

“…The used abbreviations are as following: s, singlet; d, doublet; m, multiplet. Compound 3 [41], 8a-f [46,47], 4 [48], and 6a-d [49] were synthesized in accordance with the literature procedures.…”

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

“…As shown in Figure 1, a structural hybridization approach was carried out by incorporating the pyrimidine scaffold of Meridianin E with the benzo[d] [1,3]dioxole moiety of Leucettamine B via a backbone amide linker. The pyrimidine nucleus was also substituted at positions 2 and 4 with 4-morpholinophenylamino and 4-methoxyphenoxy moieties, respectively.…”

“…Accordingly, we report our rational design, optimization, synthetic routes, in vitro and in silico biological evaluation of the newly synthesized marine-derived compounds 5a-5g. As shown in Figure 1, a structural hybridization approach was carried out by incorporating the pyrimidine scaffold of Meridianin E with the benzo[d] [1,3]dioxole moiety of Leucettamine B via a backbone amide linker. The pyrimidine nucleus was also substituted at positions 2 and 4 with 4-morpholinophenylamino and 4-methoxyphenoxy moieties, respectively.…”