Synthesis and biological activities of conformationally restricted, tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases

Journal of Medicinal Chemistry
A GangjeeS F Queener

Abstract

Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'-positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCl5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipiv...Continue Reading

References

Mar 1, 1992·Mayo Clinic Proceedings·J E Rosenblatt
Jan 24, 1992·Journal of Medicinal Chemistry·J I DeGrawF M Sirotnak
Jul 1, 1991·Antimicrobial Agents and Chemotherapy·M C Broughton, S F Queener
Feb 1, 1991·Journal of Medicinal Chemistry·E M Berman, L M Werbel
Feb 1, 1991·Journal of Medicinal Chemistry·A GangjeeJ Thorndike
Oct 1, 1987·Medicinal Research Reviews·K T Douglas
Jan 1, 1995·Annual Review of Microbiology·P Borst, M Ouellette

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Citations

Mar 29, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ahmed M Alafeefy
Feb 11, 2005·Chemical Reviews·Ivan M KompisRudolf L Then

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