title: Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway.
abstract: A novel series of 5,7-dibromoisatin analogs were synthesized and evaluated for their cytotoxicities against four human cancer cell lines including colon HT29, breast MCF-7, lung A549 and melanoma UACC903. Analogs 6, 11 and 13 displayed good in vitro anticancer activity on the HT29 human colon cancer cell line in the 1 μM range. Analogs 5, 9 and 12, containing a selenocyanate group in the alkyl chain were the most promising compounds on the breast cancer MCF-7 cell line. Biological assays relating to apoptosis were performed to understand the mechanism of action of these analogs. Compounds 5 and 6 were found to inhibit tubulin polymerization to the same extent as the anticancer drug vinblastine sulfate, but compounds 11 and 13 inhibited significantly better than vinblastine. Further western blot analysis suggested that compound 6 at 2 μM reduced both levels and phosphorylation state of Akt. Compounds 11 and 13 at 1 μM caused reduced Akt protein levels and strongly suppressed the phosphorylation of Akt. Therefore, 11 and 13 were demonstrated as efficient dual inhibitors of both tubulin polymerization and the Akt pathway and good candidates for further study. More importantly, the strategy of microtubule and Akt dual inhibitors might be a promising direction for developing novel drugs for cancer.
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033, USA. kxg21@psu.edu
authors.forename: Gowdahalli
authors.initials: G
authors.lastname: Krishnegowda
authors.forename: A S
authors.initials: AS
authors.lastname: Prakasha Gowda
authors.forename: Hephzibah Rani S
authors.initials: HR
authors.lastname: Tagaram
authors.forename: Kevin F Staveley-O'
authors.initials: KF
authors.lastname: Carroll
authors.forename: Rosalyn B
authors.initials: RB
authors.lastname: Irby
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
mesh_terms: D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D014404:Tubulin; D050257:Tubulin Modulators; D007510:Isatin; D051058:Oncogene Protein v-akt