Synthesis and in-vitro cytotoxicity evaluation of novel naphtindolizinedione derivatives, part II: improved activity for aza-analogues.

Our previous investigation on potential antitumor agents now got enriched by the evaluation of in-vitro activity against a full panel of NCI cancer cell lines for five new compounds. The concurrent presence in the molecular structure of a nitrogen atom in the aromatic system and a N,N-dimethylaminoethyl amide chain play a decisive role to enhance cytotoxicity. The N,N-anti compound 14 shows a higher activity than its N,N-syn isomer, exhibiting the best selective inhibition against the melanoma MALME-3M cell line, with a GI(50)-value (= 30 nM) corresponding to a 330-fold increase in activity compared to the corresponding deaza-analogue. Compound 14 is efficiently synthesized by aminolysis of the ester obtained as a single regio-isomer by an one-pot three-component procedure involving metal-assisted cyclization under microwave irradiation conditions.