title: Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors.
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.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jourdan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dohle
authors.forename: Meriel R
authors.initials: MR
authors.lastname: Kimberley
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter