SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF SUBSTITUTED DIHYDROBENZO[H]PYRIMIDO[4,5-B]QUINOLINES AS TETRACYCLIC 5-DEAZA NONCLASSICAL FOLATES

Novel tetracyclic compounds 1-4 have been synthesized via a regiospecific cyclocondensation reaction between substituted 6-aminopyrimidines 5-7 and chlorovinyl aldehydes 13 and 14. The linear structures of these compounds were established by H-1 nmr and C-13 nmr spectral data and also by synthesis of the compounds via an unambiguous route. The growth of Manca human lymphoma cells was inhibited 50% by 1 and 4 at 4.5 x 10(-6) M and 1.2 x 10(-6) M respectively. These compounds also inhibited human dihydrofolate reductase (DHFR) by 50% at 4.4 x 10(-6) M and 1.4 x 10(-6) M respectively and L. casei DHFR at 1.9 x 10(-5) M and 1.1 x 10(-5) M respectively. Compound 16, a positional isomer of 1, was the most potent of the compounds studied, it inhibited the growth of Manca human lymphoma cells by 50% at 9 x 10(-8) M. The IC50 values of 16 for the inhibition of human DHFR and L. casei DHFR were 8 x 10(-8) M and 1.9 x 10(-5) M respectively.