Design, Synthesis, and Biological Evaluation of Novel Selenium-Containing Isocombretastatins and Phenstatins as Antitumor Agents

Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl­(phenyl)­selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hyb...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-09, Vol.60 (17), p.7300-7314
Main Authors: Pang, Yanqing, An, Baijiao, Lou, Lanlan, Zhang, Junsheng, Yan, Jun, Huang, Ling, Li, Xingshu, Yin, Sheng
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cell Cycle Checkpoints - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Design
Drug Screening Assays, Antitumor
G2 Phase - drug effects
Humans
Male
Membrane Potential, Mitochondrial - drug effects
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Rats, Sprague-Dawley
Selenium - chemistry
Selenium - pharmacology
Selenium - therapeutic use
Stilbenes - chemistry
Stilbenes - pharmacology
Stilbenes - therapeutic use
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Summary:Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl­(phenyl)­selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC50 values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC50 values of 2–34 nM against 12 cancer cell lines, including two drug-resistant cell lines. Importantly, its phosphate salt, 11ab, inhibited tumor growth in xenograft mice models with inhibitory rate of 72.9% without apparent toxicity, which was better than the reference compounds isoCA-4P (inhibitory rate 52.2%) and CA-4P (inhibitory rate 47.6%). Mechanistic studies revealed that 11a is a potent tubulin polymerization inhibitor, which could arrest cell cycle at G2/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, 11a could serve as a promising lead for the development of highly efficient anticancer agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00480