Steroidal derived acids as inhibitors of human Cdc25A protein phosphatase.
A group of steroidal derived acids were synthesized and found to be human Cdc25A inhibitors. Their potency ranged from 1.1 to > 100 microM; the best ones compare very favorably with that of the novel cyano-containing 5,6-seco-cholesteryl acid 1 (IC50=2.2microM) reported by us recently (Peng, H.; Zalkow, L. H.; Abraham, R. T.; Powis, G. J. Med. Chem. 1998, 41, 4677). Structure-activity relationships of these compounds revealed that a hydrophobic cholesteryl side chain and a free carboxyl group are crucial for activity. The distance between these two pharmacophores is also important for the potency of these compounds. Several of the compounds showed selective growth inhibition effects in the NCI in vitro cancer cell line panel.
Peng
H
H
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332, USA.
Xie
W
W
Kim
D I
DI
Zalkow
L H
LH
Powis
G
G
Otterness
D M
DM
Abraham
R T
RT
D000143:Acids; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013057:Spectrum Analysis; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
D000143:Acids; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013256:Steroids; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases