Mc. Liu et al., SYNTHESIS AND BIOLOGICAL-ACTIVITY OF 3-AMINO AND 5-AMINO DERIVATIVES OF PYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE, Journal of medicinal chemistry, 39(13), 1996, pp. 2586-2593
A series of 3- and 5-alkylamino derivatives, as well as other structur
ally modified analogues of pyridine-2-carboxaldehyde thiosemicarbazone
, have been synthesized and evaluated as inhibitors of CDP reductase a
ctivity and for their cytotoxicity in vitro and antineoplastic activit
y 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-methyla
mino, 5-methylamino, 3-allylamino, 5-ethylamino, 5-allylamino, 5-propy
lamino, and 5-butylamino derivatives (5, 6, and 11-15), which were the
n condensed with thiosemicarbazide to yield the respective thiosemicar
bazones (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. O
xidation of 2-(1,3-dioxoian-2-yl)-4-methyl-5-nitropyridine (26) with s
elenium dioxide, followed by sequential treatment with sodium borohydr
ide, methanesulfonyl chloride, and morpholine afforded the morpholinom
ethyl derivative 30. Catalytic hydrogenation of 23 and 30 with Pd/C yi
elded the corresponding amino derivatives 24 and 31. Catalytic hydroge
nation of 5-cyano-2-methylpyridine (33) with Raney nickel, followed by
treatment with acetic anhydride, gave the amide derivative 35. N-Oxid
ation of 35, followed by rearrangement with acetic anhydride, produced
the acetate derivative, 5-[(acetylamino)methyl]-2-(acetoxymethyl)pyri
dine (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 respectiv
e 3,5-diaminopyridine-, 4-(4-morpholinylmethyl)-5-aminopyridine-, and
5-(aminomethyl)pyridine-2-carboxaldehyde thiosemicarbazones (25, 32, a
nd 40). The most biologically active compounds synthesized were the 5-
(methylamino)-, 5-(ethylamino)-, and 5-(allylamino)pyridine-2-carboxal
dehyde thiosemicarbazones (8, 17, and 18), which were potent inhibitor
s of ribonucleotide reductase activity with corresponding IC50 values-
of 1.3, 1.0, and 1.4 mu M and which produced significant prolongation
of the survival time of L1210 leukemia-bearing mice, with correspondin
g optimum % T/C values of 223, 204, and 215 being obtained when admini
stered twice daily for six consecutive days at dosages of 60, 80, and
80 mg/kg, respectively.