Effective transfer integrals ( r ) have been evaluated for u-and n-type electron and hole transfer in radical ion systems comprising methylene donor/acceptor groups linked by various saturated organic spacer groups. The T values have been calculated on the basis of ab initio self-consistent-field wave functions for the radical ion states, obtained either directly for the system of interest ( TwF) or from the associated neutral state via Koopmans' theorem (TKT), and employing either minimal (STO-3G) or split-valence (3-21G) basis sets. The TKT values have been decomposed into additive contributions from individual pathways, both through-space (Ti;) and through-bond (Ti:), using perturbation theory as formulated by Ratner together with a localized orbital basis represented by natural bond orbitals (NBO's) as defined by Weinhold et al. The overall coupling has been shown to arise from interference among a large number of competing pathways, none of which is strongly dominant. Nearest-neighbor pathways of the McConnell type are significant for transfer in some radical cation systems, but are frequently of very minor significance in comparison with lower-order superexchange pathways, often with contributions differing in sign from the overall TKT values. These latter conclusions are generally consistent with those based on studies involving different saturated spacer groups by Naleway et al. (for radical anions) and Jordan and Paddon-Row (for radical anions and cations). We find that transfer in radical anions and cations is generally dominated, respectively, by "electron" and "hole" pathways, but both mechanisms are found to be significant in both types of transfer. A number of transferability relationships have been identified for generic pathway types, and the important influence of stereochemistry on coupling has been illustrated, with regard to both orientation of donor/acceptor groups relative to the spacer and internal conformation of the spacer, showing the competition between coupling via the carbon framework and via CH bonds (i.e., hyperconjugation).
Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter c-Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Whereas 1.0 µM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation, under non-adherent conditions or when grown as spheroids or colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites-associated ovarian carcinoma tumor growth associated with the inhibition of FAK tyrosine phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments.
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