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 1 H nmr and 13 C 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 × 10 −6 M and 1.2 × 10 −6 M respectively. These compounds also inhibited human dihydrofolate reductase (DHFR)by 50% at 4.4 × 10 −6 M and 1.4 × 10 −6 irrespectively and L. casei DHFR at 1.9 × 10 −5 M and 1.1 × 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 × 10 −8 M . The IC 50 values of 16 for the inhibition of human DHFR and L. casei DHFR were 8 × 10 −8 M and 1.9 × 10 −5 M respectively.