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6-OH-Phenanthroquinolizidine Alkaloid and Its Derivatives Exert Potent Anticancer Activity by Delaying S Phase Progression.
Journal of Medicinal Chemistry 2017 April 14
To discover new phenanthroindolizidine and phenanthroquinolizidine alkaloids as potential anticancer drug candidates, non-natural 6-O-desmethylcryptopleurine (2) and its derivatives were prepared. Most of the new compounds exhibited potent antiproliferative activity against A549 and BEL-7402 cells, with the lowest IC50 being 3 nM. Optically pure 2-R was further evaluated against a panel of 30 cancer cell lines and found to inhibit the proliferation of all tested cell lines, including three multidrug-resistant cell lines, with an average IC50 value of 2.1 nM, which is much lower than that of previously reported phenanthroindolizidine DCB-3503 (1, IC50: 166.7 nM). A mechanistic evaluation showed that 2-R potently inhibited cell growth and colony formation, which are associated with a delay in S phase progression through the inhibition of DNA synthesis. These results along with further study on the safety profile of these compounds will facilitate the discovery of new phenanthroindolizidine and phenanthroquinolizidine alkaloids for use as anticancer drug candidates.
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