期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 12, 页码 1948-1954出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00505
关键词
Phenanthrene-based tylophorine analogues; lead optimization; one-pot synthesis of phenanthrenes; PBT-1; antitumor agents
资金
- NIH from the National Cancer Institute [CA177584]
- Eshelman Institute for Innovation award
Phenanthrene-based tylophorine-1 (PBT-1) and its derivatives showed significant antiproliferative activities in cellular assays, especially compounds with a 7-hydroxy group on the phenanthrene B-ring and a pendant piperidine E-ring. One compound, 9h, displayed over 4-fold higher potency against triple-negative breast cancer cells compared to estrogen-responsible breast cancer cells. The new active compounds induced cell cycle accumulation in the late S and G2/M phase, without affecting microtubule formation or cell morphology, indicating their potential as novel antitumor agents.
Phenanthrene-based tylophorine-1 (PBT-1) was identified previously as a lead compound in an anticancer drug discovery effort based on natural Tylophora alkaloids. An expanded structural optimization using a new more efficient synthetic route provided 14 PBT-derivatives. Eleven compounds displayed obvious antiproliferative activities in cellular assays (GI(50) 0.55-9.32 mu M). The most potent compounds 9c, 9g, and 9h (GI(50) < 1 mu M) contained a 7-hydroxy group on the phenanthrene B-ring in addition to a pendant piperidine E-ring with different 4-substituents. Compound 9h with NH2 as the piperidine substituent was at least 4-fold more potent against triple-negative breast cancer MDA-MB-231 than estrogen-responsible breast cancer MCF-7 cell growth. In further biological evaluations, the new active compounds induced cell cycle accumulation in the late S and G2/M phase without interfering with microtubule formation or cell morphology. These results on the optimization of the B- and E-rings of PBT-1 should benefit further development of novel antitumor agents.
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