742-91-6Relevant academic research and scientific papers
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.
Protolytic defluorination of trifluoromethyl-substituted arenes
Kethe, Anila,Tracy, Adam F.,Klumpp, Douglas A.
experimental part, p. 4545 - 4549 (2011/07/29)
A series of trifluoromethyl-substituted arenes were studied in their reactions with Bronsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid.
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.
Reactivities of triarylmethyl and diarylmethyl cations with azide ion investigated by laser flash photolysis. Diffusion-controlled reactions
McClelland, Robert A.,Kanagasabapathy,Banait, Narinder S.,Steenken, Steen
, p. 1009 - 1014 (2007/10/02)
By use of the technique of laser flash photolysis, rate constants kAz and ks have been directly measured for the reactions at 20 °C in acetonitrile-water (AN-W) solutions of varying composition of 18 triarylmethyl and 10 diarylmethyl cations with azide and solvent. The cations have ks that depend on substituent and vary from ～101 to ～107 s-1. For the more stable ions kAz also varies, increasing with decreased electron donation and also increasing by as much as 103 with increasing acetonitrile content. For less stable cations, however, the rate constant becomes independent of substituent. The break occurs when ks has reached ～105 s-1. The limiting rate constants have magnitudes in the vicinity of 1010 M-1 s-1; these do depend on solvent and type of cation, with diarylmethyl cations reacting at the limit 1.6 ± 0.2 times faster than triarylmethyl. The data can be fit by a model where there is diffusional encounter of the cation and azide to form an ion pair, with the combination within the ion pair rate-limiting for the more stable cations and the diffusion step rate-limiting for the less stable ones. The limiting rate constants represent the latter, diffusional encounter of the cation and azide. The Debye-Smoluchowski equation for diffusion-controlled reactions predicts rate constants that are larger than observed by factors of 2-2.5 for diarylmethyl and 4 for triarylmethyl. Deviations can be attributed to nonproductive encounters where the anion has approached the cation in the plane of one of the rings and thus cannot form a proper reacting configuration. The difference between the two types of cations is explained by the greater difficulty of achieving this configuration with the more sterically congested triarylmethyl cation. Ratios kAz/ks obtained from product analysis (competition kinetics) have previously been found to show adherence to the reactivity-selectivity principle. This has been interpreted (Rappoport, Jencks) in terms of the reaction with azide having reached the diffusion limit. The directly measured kAz establish that this is indeed the case. This study also validates the use of azide as a "clock" (Jencks, Richard) for converting such ratios to absolute rate constants through use of a value of 5 × 109 M-1 s-1 for kAz. The directly measured diffusion-limited kAz are somewhat larger than this, but the differences are small, at most a factor of 4.
