Synthesis and cytotoxic activities of azanaphthoquinone annelated pyrrolo hydrazone derivatives

Abstract

We are interested in the synthesis of azanaphthoquinone annelated pyrrolo hydrazone derivatives as
cytostatic compounds. The synthetic pathway was started from the commercially available 5-hydroxyisoquinoline
by 3-steps reaction to obtain 1H-pyrrolo[3,2-g]isoquinoline-4,9-dione. N-Alkylation of nitrogen atom in pyrrole
ring was carried out under basic conditions with different side chains to obtain mono-substituted azanaphthoquinone
annelated pyrroles with 2 to 4-carbon side chains in moderate to good yields. The hydrazone derivatives
were synthesized by condensation reaction of mono-substituted products 5 with hydrazine under basic conditions.
The reactions occurred regioselectively at C-4 to give products 6. The synthesized compounds were purifi ed by
column chromatography and characterized by spectroscopic techniques including 1H NMR, 13C NMR, IR, UV
and LC-MS. The antiproliferative activity of the synthesized compounds was evaluated on cervical carcinoma:
KB/HeLa by using xCELLigence from Roche. The results show that the mono-substituted products with 2-carbon
side chain (5b) exhibited a very good activity with IC50 value of 0.008 μM. The hydrazone 6a showed higher
inhibitory activity with IC50 value of 0.282 μM compared to the mono-substituted derivative 5a. The side chains
with cyclic amine are of interest for the further studies.