AZINYL AND DIAZINYL HYDRAZONES DERIVED FROM ARYL N-HETEROARYL KETONES- SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY

A series of N-heteroaryl hydrazones derived from aryl N-heteroaryl or bis-N-heteroaryl methanones was prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was establis hed by means of NMR spectroscopy. Antiproliferative activity was deter mined in a panel of human tumor cell Lines (CCRF-CEM, Burkitt's lympho ma, HeLa, ZR-75-1, HT-29, and MEXF 276L) in vitro. Generally, the new compounds were found to be more patent (IC50 = 0.011-0.436 mu M) than the ribonucleotide reductase inhibitor hydroxyurea (IC50 = 140 mu M) M ost of the compounds exhibited the highest activity against Burkitt's lymphoma with an IC50 Of 0.011-0.035 mu M. [C-14]Cytidine incorporatio n into DNA was quantitated for selected hydrazones (Z-A, E-1, Z-3, Z-4 , E-5, Z-5, E-13, E-18, Z-19, Z-24, and E-26) as a measure of the inhi bition of-ribonucleotide reductase in Burkitt's lymphoma cells. The E- configurated compounds were found to inhibit [C-14]cytidine incorporat ion to a greater extent (IC50 = 0.67-5.05 mu M) than the Z-isomers (IC 50 = 7.20 to > 10 mu M). Principal component analysis of the IC50 valu es obtained for inhibition of cell proliferation revealed that the cel l lines tested can be grouped into three main families showing differe nt sensitivities toward the compounds in our series [(i) CCRF-CEM, Bur kitt's lymphoma, and Hela; (ii) HT-29; and (iii) MEXF 276 L].