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Open AccessArticle

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

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
3
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo P.O. Box 11566, Egypt
5
Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah P.O. Box 6231, Saudi Arabia
*
Author to whom correspondence should be addressed.
Mar. Drugs 2020, 18(4), 190; https://doi.org/10.3390/md18040190
Received: 6 March 2020 / Revised: 26 March 2020 / Accepted: 29 March 2020 / Published: 2 April 2020
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 7af and 9ah 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. View Full-Text
Keywords: marine-inspired; breast cancer; bis-indoles; synthesis; apoptosis marine-inspired; breast cancer; bis-indoles; synthesis; apoptosis
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MDPI and ACS Style

Eldehna, W.M.; Hassan, G.S.; Al-Rashood, S.T.; Alkahtani, H.M.; A. Almehizia, A.; Al-Ansary, G.H. Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation. Mar. Drugs 2020, 18, 190. https://doi.org/10.3390/md18040190

AMA Style

Eldehna WM, Hassan GS, Al-Rashood ST, Alkahtani HM, A. Almehizia A, Al-Ansary GH. Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation. Marine Drugs. 2020; 18(4):190. https://doi.org/10.3390/md18040190

Chicago/Turabian Style

Eldehna, Wagdy M.; Hassan, Ghada S.; Al-Rashood, Sara T.; Alkahtani, Hamad M.; A. Almehizia, Abdulrahman; Al-Ansary, Ghada H. 2020. "Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation" Mar. Drugs 18, no. 4: 190. https://doi.org/10.3390/md18040190

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