title: Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents.
abstract: A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.
authors: Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India.
authors: Mukund K
authors: MK
authors: Gurjar
authors: Radhika D
authors: RD
authors: Wakharkar
authors: Anu T
authors: AT
authors: Singh
authors: Manu
authors: M
authors: Jaggi
authors: Hanumant B
authors: HB
authors: Borate
authors: Popat D
authors: PD
authors: Shinde
authors: Ritu
authors: R
authors: Verma
authors: Praveen
authors: P
authors: Rajendran
authors: Sarjana
authors: S
authors: Dutt
authors: Gurvinder
authors: G
authors: Singh
authors: Vinod K
authors: VK
authors: Sanna
authors: Manoj K
authors: MK
authors: Singh
authors: Sanjay K
authors: SK
authors: Srivastava
authors: Vishal A
authors: VA
authors: Mahajan
authors: Vinod H
authors: VH
authors: Jadhav
authors: Kakali
authors: K
authors: Dutta
authors: Karthik
authors: K
authors: Krishnan
authors: Anika
authors: A
authors: Chaudhary
authors: Shiv K
authors: SK
authors: Agarwal
authors: Rama
authors: R
authors: Mukherjee
authors: Anand C
authors: AC
authors: Burman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D013267:Stilbenes; D050257:Tubulin Modulators; C058728:fosbretabulin