Syntheses and Biological Activities of a Novel Group of Steroidal Derived Inhibitors for Human CDC25A Protein Phosphatase

• Published in: Journal of medicinal chemistry 2001-03, Vol.44 (5), p.834-848
• Main Authors: Peng, Hairuo, Xie, Wenge, Otterness, Diane M, Cogswell, John P, McConnell, Randy T, Carter, H. Luke, Powis, Garth, Abraham, Robert T, Zalkow, Leon H
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; cdc25 Phosphatases - antagonists & inhibitors; cdc25 Phosphatases - chemistry; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluoresceins - chemistry; General aspects; Humans; Kinetics; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Steroids - chemical synthesis; Steroids - chemistry; Steroids - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0004401

Silica gel supported pyrolysis of an azido-homo-oxa steroid led to rearrangement, presumably by a mechanism similar to that of solution phase Schmidt fragmentation, to produce a group of novel inhibitors for the oncogenic cell cycle regulator Cdc25A phosphatase. Cyano-containing acid 17, one of the best inhibitors in this group, inhibited the activity of Cdc25A protein phosphatase reversibly and noncompetitively with an IC50 value of 2.2 μM. Structure−activity relationships revealed that a phosphate surrogate such as a carboxyl or a xanthate group is required for inhibitory activity, and a hydrophobic alkyl chain, such as the cholesteryl side chain, contributes greatly to the potency. Without the cyano group, acid 26 and xanthate 27 were found to be more selective over Cdc25A (IC50 = 5.1 μM and 1.1 μM, respectively) than toward CD45 (IC50 > 100 μM, in each case), a receptor protein tyrosine phosphatase. Several of these inhibitors showed antiproliferative activities in the NCI 60-human tumor cell line screen. These steroidal derived Cdc25 inhibitors provide unique leads for the development of dual-specificity protein phosphatase inhibitors.