Synthesis and biological activity of N4-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents

Abstract

A series of eight N 4 -phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo [2,3-d] pyrimidine-2,4-diamines 8-15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N 4 -phenylsubstituted-6-phenylmethylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines 16-20 were synthesized to evaluate the importance of the 2-NH 2 moiety for multiple receptor tyrosine kinase (RTK) inhibition. Cyclocondensation of α-halomethylbenzylketones with 2,6-diamino-4-hydroxypyrimidine afforded 2-amino-6-(2,4-dichlorophenylmethyl)-3,7-dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one, 23 and reaction of α-bromomethylbenzylketones with ethylamidinoacetate followed by cyclocondensation with formamide afforded the 6-phenylmethylsubstituted-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones, 40-42 respectively. Chlorination of the 4-position and displacement with appropriate anilines afforded the target compounds 8-20. Compounds 8, 10 and 14 were potent VEGFR-2 inhibitors and were 100-fold, 40-fold and 8-fold more potent than the standard semaxanib, respectively. Previously synthesized multiple RTK inhibitor, 5 and the VEGFR-2 inhibitor 8 from this study, were chosen for further evaluation in a mouse orthotopic model of melanoma and showed significant inhibition of tumor growth, angiogenesis and metastasis.

Antitumor activity of novel pyrrolo[2,3-d]pyrimidin-4-ones

“…We also explored the role of apoptosis on cancer cell lines. Pyrrolo[2,pyrimidine is known to have a broad spectrum of biological activities, including antitumor activity (Jung et al, 2009;Abou El Ella et al, 2007;Gangjee et al, 2010), so some new 2-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones have been prepared through cyclocondensation of 2-amino-1H-pyrrole-3carboxamides with aromatic aldehydes, followed by air oxidation in the presence of 3-methyl-1-(4-sulfonic acid) butylimidazolium hydrogen sulfate [(CH 3 ) 4 SO 3 HMIM] [HSO 4 ], a Brønsted-acid ionic liquid, as a green, reusable catalyst in solvent-free conditions (Davoodnia et al, 2010) (Scheme 1).…”

Pyrrolopyrimidine: A Versatile Scaffold for Construction of Targeted Anti-cancer Agents

“…In 2010 in an attempt to structurally design either a dual EGFR/VEGFR-2 inhibitor or even a selective VEGFR-2 inhibitor, (Compound 43) was previously synthesized as multiple RTK inhibitor, and the VEGFR-2 inhibitor (Compound 47), were chosen for further evaluation and showed significant inhibition of tumor growth, angiogenesis and metastasis. 136 …”

Convenient Synthesis and Antibacterial Activity of Tricyclic Azine Derivatives

“…The well known diverse biological activities of compounds containing pyridines and pyrimidines as components of fused azines [8][9][10][11][12][13][14][15][16]21,[22][23][24][25][26][27][28] prompted us to test and study the antibacterial activities of some of the newly synthesised products. Table 1 shows that most of the tested compounds had moderate to high activity against all four microorganisms.…”