A series of 3- and 5-alkylamino derivatives, as well as other structurally modified analogues of
pyridine-2-carboxaldehyde thiosemicarbazone, have been synthesized and evaluated as inhibitors of
CDP reductase activity and for their cytotoxicity in vitro and
antineoplastic activity in vivo against the
L1210 leukemia. Alkylation of 3- and 5-amino-2-(1,3-dioxolan-2-yl)pyridines (1, 2) resulted in corresponding 3-methylamino, 5-methylamino, 3-allylamino, 5-ethylamino, 5-allylamino, 5-propylamino, and 5-butylamino derivatives (5, 6, and 11-15), which were then condensed with
thiosemicarbazide to yield the respective
thiosemicarbazones (7, 8, and 16-20). Oxidation of 3,5-dinitro-2-methylpyridine (21) with
selenium dioxide, followed by treatment with
ethylene glycol and
p-toluenesulfonic acid, produced the cyclic
ethylene acetal, 23. Oxidation of 2-(1,3-dioxolan-2-yl)-4-methyl-5-nitropyridine (26) with
selenium dioxide, followed by sequential treatment with
sodium borohydride,
methanesulfonyl chloride, and
morpholine afforded the morpholinomethyl derivative 30. Catalytic hydrogenation of 23 and 30 with Pd/C yielded the corresponding amino derivatives 24 and 31. Catalytic hydrogenation of 5-cyano-2-methylpyridine (33) with Raney
nickel, followed by treatment with
acetic anhydride, gave the
amide derivative 35. N-Oxidation of 35, followed by rearrangement with
acetic anhydride, produced the
acetate derivative, 5-[(acetylamino)methyl]-2-(acetoxymethyl)
pyridine (37). Repetition of the N-oxidation and rearrangement procedures with compound 37 yielded the diacetate derivative 39. Condensation of compounds 24, 31, and 39 with
thiosemicarbazide afforded the respective 3,5-diaminopyridine-, 4-(4-morpholinylmethyl)-5-aminopyridine-, and 5-(aminomethyl)pyridine-2-carboxaldehyde
thiosemicarbazones (25, 32, and 40). The most biologically active compounds synthesized were the 5-(methylamino)-, 5-(ethylamino)-, and 5-(allylamino)pyridine-2-carboxaldehyde
thiosemicarbazones (8, 17, and 18), which were potent inhibitors of
ribonucleotide reductase activity with corresponding IC50 values of 1.3, 1.0, and 1.4 microM and which produced significant prolongation of the survival time of
L1210 leukemia-bearing mice, with corresponding optimum % T/C values of 223, 204, and 215 being obtained when administered twice daily for six consecutive days at dosages of 60, 80, and 80 mg/kg, respectively.