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.
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.
Gurjar
Mukund K
MK
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India.
Wakharkar
Radhika D
RD
Singh
Anu T
AT
Jaggi
Manu
M
Borate
Hanumant B
HB
Shinde
Popat D
PD
Verma
Ritu
R
Rajendran
Praveen
P
Dutt
Sarjana
S
Singh
Gurvinder
G
Sanna
Vinod K
VK
Singh
Manoj K
MK
Srivastava
Sanjay K
SK
Mahajan
Vishal A
VA
Jadhav
Vinod H
VH
Dutta
Kakali
K
Krishnan
Karthik
K
Chaudhary
Anika
A
Agarwal
Shiv K
SK
Mukherjee
Rama
R
Burman
Anand C
AC
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
D000970:Antineoplastic Agents; D003517:Cyclopentanes; D013267:Stilbenes; D050257:Tubulin Modulators; C058728:fosbretabulin