Joseph Guiles

Chiral formamidines. Asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines.

Abstract Use of a modified auxiliary allowed for the asymmetric synthesis of quaternary carbons adjacent to nitrogen in tetrahydroisoquinolines.

Chiral lithio formamidines. Are they configurationally stable

Abstract Metalation and alkylation of an optically active 1-methyl isoquinoline in the presence of an achiral formamidine leads to completely racemic material.

In vitro characterization of a novel series of platelet-derived growth factor receptor tyrosine kinase inhibitors

In this report, we describe the discovery and characterization of a novel biarylhydrazone series of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors typified by the prototype WIN 41662 (3-phenyl-N1-[1-(4-pytidyl)pyrimidine]hydrazone). WIN 41662 inhibited PDGF-stimulated autophosphorylation of PDGF receptors from human vascular smooth muscle cells (hVSMC) with an IC50 value of 60 nM. The inhibitor appeared to be competitive with respect to substrate (Mn(2+)-ATP), having a calculated Ki of 15 +/- 5 nM. WIN 41662 was approximately 500-fold more potent in inhibiting the PDGF receptor tyrosine kinase than the p56lck tyrosine kinase. It was inactive against other serine/threonine and tyrosine kinases tested. WIN 41662 produced concentration-dependent inhibition of PDGF-stimulated receptor autophosphorylation in intact hVSMC with an IC50 < 100 nM. Intracellular Ca2+ mobilization and cell proliferation were events that occurred in hVSMC subsequent to PDGF receptor activation. WIN 41662 inhibited PDGF-stimulated Ca2+ mobilization and cell proliferation ([3H]TdR incorporation) with IC50 values of 430 nM and 2.3 microM, respectively. These effects appeared to be specifically related to PDGF receptor tyrosine kinase inhibition since WIN 41662 was not cytotoxic (in vitro) and since WIN 72039, a close structural analog that does not inhibit PDGF receptor tyrosine kinase, also did not inhibit PDGF-stimulated receptor autophosphorylation, Ca2+ mobilization, or hVSMC proliferation. Thus, WIN 41662 is representative of a novel class of selective PDGF receptor tyrosine kinase inhibitors that inhibit PDGF-regulated secondary events in intact cells.

Grignard cross-coupling amenable to large scale production of alpha-fluorostyryl and alpha-fluorovinylthiophenes.

An efficient nickel-catalyzed Kumada-Corriu cross coupling enabled the introduction of an alpha-fluorovinyl functionality with excellent conversion and specificity.

Chiral formamidines. The mechanism of mono- and di-alkylation leading to chiral, non-racemic tetrahydroisoquinolines

Abstract The effect on facial selectivity and degree of stereoselectivity by varying the size of the chiral auxiliary allows a mechanism for alkylation to be presented.

A convenient asymmetric synthesis of pyrrolo[2,1-a]isoquinolines

Abstract A four-step synthesis of optically pure 6α-phenyl pyrroloisoquinolines from chiral formamidines has been accomplished.