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.
Highlights
Drug discovery from marine sources is a prehistoric praxis
In Scheme 1, the Fischer esterification procedure was scrutinizing the results of cell cycle analysis unraveled that these compounds arrest the cell applied to 3-indoleacetic acid 3 [19] to afford methyl 1H-indole-2-carboxylate 4, which subsequently cycle in the G0/G1 phase
The results revealed that, in contrast to the results observed for the antiproliferative activity against MCF-7 cell line, the bromo substitution of the oxindole ring was advantageous for the activity as compound 9g (IC50 = 2.85 μM) proved to be 1.5-times more potent than its unsubstituted bioisostere 9d, compound 9h (IC50 = 2.29 μM)
Summary
Drug discovery from marine sources is a prehistoric praxis. Surveying the literature reveals that the anticancer activity of diverse bis-indole compounds. Mar. Drugs 2020, 18, 190; doi:10.3390/md18040190 www.mdpi.com/journal/marinedrugs. Mar. Drugs 2020, 18, 190 extracted from marine sources including plants, fungi, algae, and marine mollusks was broadly discussed in diverse manuscripts [1,2]. Diverse substituted indole and bis-indole derivatives extracted from marine sources have been shown to exhibit significant antiproliferative activity [3,4]. Edwards et al [5] conducted a study on purified 6-bromoisatin (Figure 1) extracted from the Australian marine mollusk Dicathais orbita known for its antineoplastic activity. The study revealed that 6-bromoisatin markedly reduced the proliferation and concomitantly induced apoptosis in human colon cancer cell lines HT29 and
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
