Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors
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- 作者：Mathew P. Leese ; Fabrice Jourdan ; Wolfgang Dohle ; Meriel R. Kimberley ; Mark P. Thomas ; Ruoli Bai ; Ernest Hamel ; Eric Ferrandis ; Barry V. L. Potter
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：3
- 期：1
- 页码：5-9
- 全文大小：259K
- 年卷期：v.3,no.1(January 12, 2012)
- ISSN：1948-5875
文摘
Structure鈥揳ctivity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative 6c through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., 9c) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties.r>