1. SAR-guided development of indole-matrine hybrids as potential anticancer agents via mitochondrial stress/cytochrome c/caspase 3 signaling pathway.
- Author
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Li L, Li J, Ma L, Shang H, and Zou Z
- Subjects
- Humans, Cytochromes c metabolism, Matrines, Caspase 3 metabolism, Cell Line, Tumor, Apoptosis, Signal Transduction, Cell Proliferation, Membrane Potential, Mitochondrial, Caspases metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry
- Abstract
Matrine is a clinically used adjuvant anticancer drug, yet its mild potency limited its application. To improve the anticancer activity of matrine, a total of 31 indole-matrine hybrids were constructed in four rounds of SAR-guided iterative structural optimization process. All of the synthesized compounds were evaluated for their antiproliferative activities against a panel of four human cancer cell lines (Hela, MCF-7, SGC-7901, HepG2) and two normal cell lines (GES-1, LO2). The most active hybrid 8g exhibited the anticancer IC
50 values of 0.9 to 1.2 μM, which was 3-magnitude of orders more potent than matrine. 8g also showed better selectivity towards cancer cells with the selectivity index value raised from 1.5 to 6.2. Mechanistic studies demonstrated a mitochondrial distribution for 8g by intracellular click chemistry approaches, which led to the discovery that 8g strongly induced mitochondrial stress, as evidenced by impaired energy metabolism, depolarized mitochondrial membrane potential, overload of mitochondrial calcium and escalated ROS production. 8g-induced mitochondrial stress further led to the release of cytochrome c and subsequent activation of caspase 3, which significantly promoted cellular death and inhibited colony formation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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