No abstract

A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by "piggy-backing" on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure-activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC 50 value of 25 nM and a whole cell H-Ras processing IC 50 value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π-π stacking interaction with the Y361β residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.

No abstract

Polyphenyl derivativesPolyphenyl derivatives Q 0700Oxidative Dimerization: Pd(II) Catalysis in the Presence of Oxygen Using Aqueous Media. -Oxidative dimerization of aryl boronic acids using molecular oxygen in the presence of Pd(II) as the catalyst provides an efficient synthesis of biaryls. In a number of cases addition of a phase transfer catalyst results in significant improvement. The methodology can be extended to the preparation of (E,E)-dienes [cf. (IV)]. -(PARRISH, J. P.; JUNG, Y. C.; FLOYD, R.