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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Leese MP,Jourdan F,Dohle W,Kimberley MR,Thomas MP,Bai R,Hamel E,Ferrandis E,Potter BVdoi
10.1021/ml200232csubject
Has Abstractpub_date
2012-01-12 00:00:00pages
5-9issue
1issn
1948-5875journal_volume
3pub_type
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