Synthesis and Structure−Activity Relationships of Pyrazine-Pyridine Biheteroaryls as Novel, Potent, and Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors

Abstract

There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Palladium-catalyzed C-C bond, C-N bond formation reactions were used to assemble various pyrazine-pyridine biheteroaryls as potent VEGFR-2 inhibitors. Among them, 4-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-ylamino}-butan-1-ol (39) and N-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-yl}-N',N'-dimethyl-ethane-1,2-diamine (41) exhibited the highest kinase selectivity against fibroblast growth factor receptor kinase, platelet-derived growth factor receptor kinase, and glycogen synthase kinase-3. All of these compounds showed good cellular potency to inhibit VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) but with modest effects on the unstimulated growth of HUVEC. The low inhibition of these compounds to the growth of tumor cell lines, such as HeLa, HCT-116, and A375 further confirms that these VEGFR-2 inhibitors are not cytotoxic agents. The in vivo antitumor activity of 39 and 41 were demonstrated in the A375 human melanoma xenograft nude mice model. Molecular modeling (QSAR analysis) was conducted in an attempt to rationalize the observed structure-activity relationship.

Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

“…The specific role of the bioactivity of pyridine ring has been recognized and the introduction of some pyridine analogs into the molecules of drugs could result in new compounds that have significant biological activity compared with the parent compounds Straub et al, 1997;Bolognese et al, 2002;Tiwari et al, 2002;Kuo et al, 2005). It was also reported that a diverse array of naturally occurring alkaloids in sponges exhibit potent bioactivities because of the presence of a pyridine moiety (Vincent et al, 1997;Gordon et al, 2005).…”

IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo

“…Other halogen-containing compounds are the inhibitors of VEGFR-2 ZD4190, ZD6474, PTK787 and KRN951, and the bromotyrosine aeroplysinin-1 isolated from several marine sponges (3,23). Structure-function studies with quinazolinamino-benzoquinones and pyrazine-pyridine biheteroaryls reveal that halogen substitution increases the activity of the compounds as inhibitors of the kinase domain of VEGFR-2 (24,25). Although evidences point out to the relevance of electron-withdrawing halogen substituents in the antiangiogenic inhibitor molecules, their role in the mechanism of the reaction involved in the inhibition of the receptor tyrosine kinase activity remains obscure and deserves further studies.…”

In Silico Prediction of Inhibition Activity of Pyrazine–Pyridine Biheteroaryls as VEGFR‐2 Inhibitors Based on Least Squares Support Vector Machines

“…The studied dataset was taken from the published work [17]. The 32 compounds investigated are listed in Table 1.…”

“…Generally, RNB reflects the p electron density of the molecule and hence influences the interaction between the drug and its receptor. Though NH of the side chain, directly attached to the biheteroaryl, is a hydrogenbond donor site [17]. Considering the structures as a whole, N atom mostly serves as a hydrogen-bond acceptor and more hydrogen-bond donors must come from the receptor.…”

“…Among them, a set of pyrazine -pyridine biheteroaryls was reported by Kuo et al [17], as inhibitors of VEGFR-2, and molecule modeling [Quantitative Structure -Activity Relationship (QSAR) analysis] was constructed in an attempt to rationalize the observed structure -activity relationship. Though a QSAR model was built, the results were expressed only by "RECALL".…”