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Steroidomimetic tetrahydroisoquinolines for the design of new microtubule disruptors


Reference:

Leese, M. P., Jourdan, F., Dohle, W., Kimberley, M. R., Thomas, M. P., Bai, R., Hamel, E., Ferrandis, E. and Potter, B. V. L., 2012. Steroidomimetic tetrahydroisoquinolines for the design of new microtubule disruptors. ACS Medicinal Chemistry Letters, 3 (1), pp. 5-9.

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Official URL:

http://dx.doi.org/10.1021/ml200232c

Abstract

Structure-activity 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.

Details

Item Type Articles
CreatorsLeese, M. P., Jourdan, F., Dohle, W., Kimberley, M. R., Thomas, M. P., Bai, R., Hamel, E., Ferrandis, E. and Potter, B. V. L.
DOI10.1021/ml200232c
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code28924

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