SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF 3-AMINO-N-PHENYL-1H-INDAZOLE-1-CARBOXAMIDES

Recently our research group has reported the synthesis of some 3-amino-N-phenyl-1H-indazole-1-carboxamides able to inhibit at low micromolar concentrations the cell growth of many neoplastic cell lines. The above compounds are unsubstituted in the indazole nucleus and this gives the hope to obtain more active compounds if appropriate substituents are beared by the above nucleus. So, several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanates 3a,b with 3-amino-1H-indazoles 2c,e,g, or 1H-indazole 2l respectively. Chemical trasformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamides 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamides 4i,j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamides 6a,b were prepared by acethylation of 4i,j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against 60 human tumoral cell lines derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI50 values in the 0.041-33.6 μM range, being very effective against colon and melanoma cell lines. Compound 1c induced an increase of cells in G0-G1 peak and a decrease of cells in S and G2-M phases when used at a concentration of or higher than 40µM which is the TGI calculated after 24 h of 1c exposure. This could be due to a block of G1-S transition as indicated by the ability of 1c to increase the hypophosphorylate pRb/ total pRb ratio.