742-91-6Relevant articles and documents
Triphenylbutanamines: Kinesin spindle protein inhibitors with in vivo antitumor activity
Wang, Fang,Good, James A. D.,Rath, Oliver,Kaan, Hung Yi Kristal,Sutcliffe, Oliver B.,MacKay, Simon P.,Kozielski, Frank
supporting information; experimental part, p. 1511 - 1525 (2012/04/10)
The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kiapp ≥ 10 nM and GI50 ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.
Acidities and Homolytic Bond Dissociation Energies (BDEs) of Benzyl-Type C-H Bonds in Sterically Congested Substrates
Bordwell, F. G.,Cheng, Jin-Pei,Satish, A. V.,Twyman, Cary L.
, p. 6542 - 6546 (2007/10/02)
Equilibrium acidities in DMSO and BDEs for the benzylic C-H bonds are reported for 19 triphenylmethanes, three 9,10-dihydroanthracenes, and nine xanthenes.The phenyl groups in triphenylmethane, 9-phenyl-9,10-dihydroanthracene, and 9-phenylxanthene are shown to be constrained in their ability to delocalize either the negative charges in the anions formed by loss of a proton or the odd electrons released by loss of hydrogen atom.Analysis of the pKHA values showed, however, that strong solvation of para electron-withdrawing substituents in a phenyl ring of each of these substrates caused the corresponding anion to adopt a conformation where effective conjugative overlap occured between the substituent and the carbanion via the phenyl ring.In other words a conformational change was induced via a substituent solvation assisted resonance (SSAR) effect.In sharp contrast to these large solvation-induced substituent effects on anion stabilities, remote substituent effects on radical stabilities in these congested species were found to be negligible.Substitution of either a p-toluenesulfonyl or CN group into the 9-position of xanthene caused a large increase in acidity, but the p-CH3C6H4SO2 group caused an increase in the BDE of the acidic C-H bond, whereas the CN group caused a small decrease.
