H. D. Hollis Showalter

Biochemical and cellular effects of c-Src kinase-selective pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors

Increased expression or activity of c-Src tyrosine kinase has been associated with the transformed phenotype in tumor cells and with progression of neoplastic disease. A number of pyrido[2, 3-d]pyrimidines have been characterized biochemically and in cells as part of an assessment of their potential as anti-tumor agents. The compounds were ATP-competitive inhibitors of c-Src kinase with IC(50) values < 10 nM and from 6 to >100-fold selectivity for c-Src tyrosine kinase relative to basic fibroblast growth factor receptor (bFGFr) tyrosine kinase, platelet-derived growth factor receptor (PDGFr) tyrosine kinase, and epidermal growth factor receptor (EGFr) tyrosine kinase. The compounds yielded IC(50) values < 5 nM against Lck. Human colon tumor cell growth in culture was inhibited, as was colony formation in soft agar at concentrations < 1 microM. Phosphorylation of the c-Src cellular substrates paxillin, p130(cas), and Stat3 was also inhibited at concentrations < 1 microM. Autophosphorylation of EGFr tyrosine kinase or PDGFr tyrosine kinase was not inhibited by c-Src inhibitors, thus showing the selective nature of the compounds in cells. In a mitogenesis assay measuring thymidine incorporation stimulated by specific mitogens, the c-Src tyrosine kinase inhibitors reduced incorporated thymidine in a manner consistent with previously reported roles of c-Src in mitogenic signaling. Progression through the cell cycle was inhibited at G(2)/M in human colon tumor cells treated with two of the c-Src-selective compounds, which is also consistent with earlier reports describing a requirement for active c-Src tyrosine kinase for G(2) to M phase progression. The compounds described here are selective inhibitors of c-Src tyrosine kinase and have antiproliferative effects in tumor cells consistent with inhibition of c-Src.

Small molecule inhibitors of tumor-promoted angiogenesis, including protein tyrosine kinase inhibitors.

Angiogenesis is an exciting and promising new area of research. The concept that tumor cells are absolutely dependent upon neovascularization to grow and metastasize has opened the door to a multitude of new approaches and targets for developing anticancer therapies. These potential new antiangiogenic therapies offer the possibility for improved efficacy and reduced toxicity relative to conventional cancer treatments without the possibility of drug resistance. In particular, reports of small molecule inhibitors of tumor-promoted angiogenesis are appearing ever more frequently in the scientific literature. For this reason, the major focus of this review will be to cover small molecule inhibitors of tumor-promoted angiogenesis. The present review concentrates on selected literature, principally from mid-1996 to mid-1998, where there are sufficient biological data to support claims of antiangiogenic activities by small molecules. In addition, a historical background is presented and some of the important issues related to this field are discussed within.

SMALL MOLECULE INHIBITORS OF THE PLATELET-DERIVED GROWTH FACTOR RECEPTOR, THE FIBROBLAST GROWTH FACTOR RECEPTOR, AND SRC FAMILY TYROSINE KINASES

The inhibition of tyrosine kinases involved in growth factor signal transduction pathways represents an attractive strategy for controlling aberrant cellular growth. Over the last 4-5 years, there have been numerous reports on the discovery of small molecule inhibitors for potential therapeutic applications to a number of proliferative diseases, principally cancer and restenosis, where the over-expression of certain tyrosine kinases has been demonstrated. These include, amongst others, the platelet-derived growth factor receptor, the fibroblast growth factor receptor, and the nonreceptor c-Src tyrosine kinase. This review compiles published reports and patent filings from 1995 to mid-1997 that include data directly related to inhibition of the platelet-derived growth factor receptor, fibroblast growth factor receptor, and Src family tyrosine kinases. Potential clinical applications for selected classes of tyrosine kinase inhibitors reviewed herein will likely depend on the demonstration of meaningful activity in a variety of therapeutic targets in animal models.

Preparation of N,N′-bis(aryl)guanidines from electron deficient amines via masked carbodiimides

Abstract Preparation of N,N ′-bis(aryl)guanidines by alkylation of electron deficient amines with trityl protected carbodiimides is described. Also reported is a method for the dehydration of N -trityl- N ′-aryl ureas to the corresponding carbodiimides using the Burgess reagent.

A Novel Synthesis of 2,3-Disubstituted Benzopyran-4-ones and Application to the Solid Phase

Abstract The development of a novel synthesis of 2,3-disubstituted benzopyran-4-ones and application to the solid phase are reported. Following model studies using benzyl alcohol as a surrogate for polystyrene hydroxymethyl resin, we utilized our previously established traceless diisopropylsilyloxy linker methodology to synthesize a small library of target benzopyranones in generally high yield and purity.

Studies related to the total synthesis of pentostatin: An efficient, regiospecific glycosylation of 6,7-dihydroimidazo[4,5-d][1,2]diazepin-8(3H)-one and related homologs.

Abstract A much improved glycosylation procedure for fhe synthesis of pentostatin-like nucleosides is described.

A facile synthesis of functionalized 9,10- anthracenediones via tosylate and triflate phenolic activation

Abstract Reaction of 1,4-dihydroxy-9,10-anthracenedione bistosylates and bistriflates with a range of common nucleophiles is discussed.

1-oxo-3-aryl-1H-indene-2-carboxylic acid derivatives as selective inhibitors of fibroblast growth factor receptor-1 tyrosine kinase

Abstract Fibroblast growth factor receptor (FGFr) mediated signal transduction is implicated in vascular proliferative diseases and some cancers. We have identified methyl 1-oxo-3-phenyl-1H-indene-2-carboxylic ester as a small molecule inhibitor of the tyrosine kinase activity of FGFr-1, (IC50 = 5.1 μM). We report here the synthesis and structure-activity studies about this template core. Additionally, screening of this series against a panel of tyrosine kinases shows selective inhibition of FGFr.

Synthesis of 7-substituted 3-aryl-1,6-naphthyridin-2-amines and 7-substituted 3-aryl-1,6-naphthyridin-2(1H)-ones via diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines

The preparation of 3-aryl-7-halo-1,6-naphthyridin-2-amines and 3-aryl-7-halo-1,6-naphthyridin-2(1H)-ones from the diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines is reported. The reactions were investigated in various solvents (concentrated HCl, 50% HBF4, 70% HF–pyridine, 20% and 90% H2SO4, dilute HCl, and neat TFA). By appropriate choice of solvent and other conditions, good yields of the target compounds could be obtained, although in some cases a variety of different side products was also produced. Subsequent displacement of the 7-halogen substituents with alkylamines provides a route to more complex 7-substituted 1,6-naphthyridine derivatives that are potential tyrosine kinase inhibitors.