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Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin

Wipf, P and Minion, DJ and Halter, RJ and Berggren, MI and Ho, CB and Chiang, GG and Kirkpatrick, L and Abraham, R and Powis, G (2004) Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin. Organic and Biomolecular Chemistry, 2 (13). 1911 - 1920. ISSN 1477-0520

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Abstract

A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wipf, Ppwipf@pitt.eduPWIPF
Minion, DJ
Halter, RJ
Berggren, MI
Ho, CB
Chiang, GG
Kirkpatrick, L
Abraham, R
Powis, G
Date: 7 July 2004
Date Type: Publication
Journal or Publication Title: Organic and Biomolecular Chemistry
Volume: 2
Number: 13
Page Range: 1911 - 1920
DOI or Unique Handle: 10.1039/b405431h
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1477-0520
MeSH Headings: Alkylation; Androstadienes--chemistry; Androstadienes--pharmacology; Androstenes--chemical synthesis; Androstenes--chemistry; Androstenes--pharmacology; Androstenes--toxicity; Bacteriocins--chemical synthesis; Bacteriocins--chemistry; Bacteriocins--pharmacology; Bacteriocins--toxicity; Cell Line, Tumor; Cell Proliferation--drug effects; Humans; Inhibitory Concentration 50; Molecular Structure; Phosphatidylinositol 3-Kinases--antagonists & inhibitors; Phosphatidylinositols--chemistry; Phosphatidylinositols--metabolism; Protein Kinase Inhibitors--chemical synthesis; Protein Kinase Inhibitors--chemistry; Protein Kinase Inhibitors--pharmacology; Substrate Specificity
PubMed ID: 15227545
Date Deposited: 30 Jan 2014 18:14
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/20421

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