Tyrosine kinase inhibitors biological activity

Other biologically active bromotyrosine-derived metabolites of marine origin include aeroplysinin, Fig. (48) as cytotoxic and tyrosine kinase inhibitor [382,383], fistularin isolated from Aplysina circheri which exhibited antiviral activity [384], and ceratinamides A and B, antifouling metabolites from Pseudoceratina purpurea [385],... 

The quinazoline moiety is present in a variety of biologically active compounds that are known to interact with G-protein-coupled receptors and enzymes [177-181]. In addition, quinazolines are often used as tyrosine kinase inhibitors... 

Bursi, R., Verwer, P., Gazit, A., Beccari, A.R., Uccello Beretta, G., Balzano, F. and Guccione, S. (2001) From molecular spectra to biological activities a comparative spectra analysis (CoSA) study on epidermal growth factor receptor protein tyrosine kinase inhibitors, in Rational Approaches to Drug Design (eds H.-D. Hdltje and W. Sippl), Prous Science, Barcelona, Spain, pp. 211-213. 

Protein tyrosine phosphatases play a crucial role in the control of the activity of receptor tyrosine kinases, nonreceptor tyrosine kinases, and the signaling pathways that they regulate. The importance of the tyrosine phosphatases for receptor tyrosine kinase signaling is illustrated by the observation that virtually all receptor tyrosine kinases can be activated, even in the absence of ligand, by treatment of cells with tyrosine phosphatase inhibitors, demonstrating that the activity of tyrosine kinases is continuously controlled by inhibitory tyrosine phosphatase action. As outlined above, the activity of most receptor tyrosine kinases is positively controlled by Tyr-phosphorylation in the activation loop. Protein tyrosine phosphatases that remove these stimulatory phosphate residues will inhibit receptor activity and the biological responses mediated by Tyr-phosphorylation-dependent signaling pathways. 

Heterocycle-fused acridines possess a variety of biological activities, including Ca releasing, antiviral (e.g., anti-HIV), antimicrobial (e.g., anti-amebic and antiplasmodium) and antitumor properties. They are also enzyme inhibitors (e.g., topoisomerase II inhibitors and protein tyrosine kinase inhibitors) and have DNA-intercalation and metal-chelating properties. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases. A series of Pyrrolo [3,2-c] pyridine-4-one 2-indolinone derivatives as tyrosine kinase inhibitors were designed and synthesized. They were found to inhibit the tyrosine kinase activity associated with vascular endothelial growth factor receptor 2(VEGF-R2). Their biological evaluation results and structure-activity relationship will be discussed. 

An oxime derivative of indirubin (a natural bis-indole alkaloid used in traditional Chinese medicine to treat chronic myelocytic leukemia), indirubin-3 -monoxime (37), was found to be a potent inhibitor of cyclin-dependent kinases (CDKs), and of the proliferation of myeloid leukemia cells via inhibition of a tyrosine kinase . The 3D structure of the complex of 37 with CDK revealed that the oxime function is intact, and that it occupies the ATP-ribose site of the CDK-ATP structure. While the specific role of the oxime group in the biological activity of 37 is not clear, it was proposed that its reactivity may be utilized for further drug design... 

Vanadate (VOj or H2VO4 ) was first recognized in 1979 as having insulin mimetic properties [258]. Since then, vanadate and vanadyl (V ) have been shown to mimic most but not all biological actions of insulin in vitro and to lower blood glucose in streptozotocin-treated rats [259, 260]. Vanadate is a potent inhibitor of phosphotyrosine phosphatases, an interesting activity since the insulin receptor is a tyrosine kinase, and some of the actions of insulin have been proposed to take place via autophosphorylation of the insulin receptor and phosphorylation of cellular substrates on tyrosine residues [261]. Some recent developments on the mechanism and the in vivo activity of vanadate and its derivatives are presented here. 

Figure 10.16 Three inhibitors of PDGF receptor tyrosine kinase, their oral bioavailabilities in rat as noted on days 1 and 4 of dosing, and whether or not they induced rat CYPs (He, W., et al. Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2 the synthesis and biological activities of RPR127963, an orally bioavailable inhibitor. Bioorg. Med. Chem. Lett. 2003, 75, 3097-3100.)...

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