2. Academic Validation
  3. 6-OH-Phenanthroquinolizidine Alkaloid and Its Derivatives Exert Potent Anticancer Activity by Delaying S Phase Progression

6-OH-Phenanthroquinolizidine Alkaloid and Its Derivatives Exert Potent Anticancer Activity by Delaying S Phase Progression

  • J Med Chem. 2017 Apr 13;60(7):2764-2779. doi: 10.1021/acs.jmedchem.6b01502.
Yuxiu Liu 1,  Lihua Qing 2,  Chuisong Meng 1,  Jiajie Shi 2,  Yan Yang 2,  Ziwen Wang 1,  Guifang Han 1,  Yi Wang 2,  Jian Ding 2,  Ling-Hua Meng 2,  Qingmin Wang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University , Tianjin 300071, P. R. China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, P. R. China.
PMID: 28333459 DOI: 10.1021/acs.jmedchem.6b01502
Abstract

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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