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Synthesis and antitumour activity of certain pyridol[2,3-d] pyrimidine and 1,8-naphthyridine derivatives

Posted on 24. March, 2014.

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In an effort to establish new candidates with improved anticancer activity, we report here the synthesis of various series of 2,4,5,7-tetrasubstituted pyrido[2,3-d ]pyrimidines and their related isosteres substituted 1,8-naphthyridines. The cytotoxic activity of the newly synthesised compounds against human breast cancer cell line, MCF7 was investigated.

Most of the tested compounds exploited potent to moderate growth inhibitory activity, in particular 7-(4-chlorophenyl)-5-(3-nitrophenyl)pyrido[2,3-d ]pyrimidin-4-amine exhibited superior potency to the reference drug doxorubicin (IC50 = 7.54 and 8.48 µM respectively).

The pyrido[2,3-d]pyrimidine ring system are an interesting class of heterocycles because of several biological activities associated with this scaffold such as antibacterial, anti-inflammatory, antihypertensive, diuretic, antihistaminic and more specifically as cytotoxic agents. Their cytotoxic activities might be attributed to inhibition of several enzymes such as tyrosine kinases, cyclin-dependant kinase (CDK) and dihydrofolate reductase (DHFR). In a clinical study, the second generation dihydrofolate reductase inhibitor piritrexim (PTX), 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine, has been developed as a potent small-molecule inhibitor that is effective against cancer cells resistant to methotrexate. Piritrexim was active against a broad range of tumours, with evidence of high tissue penetration due to its lipophilicity. Also, lometrexol (5,10-dideazatetrahydrofolic acid) was a new antifolate. One of the most promising preclinical features of lometrexol in animal models was its significant activity against a broad panel of solid tumours. 

Read the full article in Journal of Chemical Research, Number 3, March 2014, pp. 147-153


DOI: 10.3184/174751914X13910886393992