Synthesis and In Vitro Evaluation of Some Novel Nucleoside analogs and DNA lntercalators as Potential Anticancer or Antiviral Agents

Thiadiazoles can be considered as analogs of pyrimidines because of the well
known analogy between a -CH=CH- group in benzenoid hydrocarbons and bivalent
sulfur, -S-, in aromatic heterocycles. Therefore, 5-amino-2H-1 ,2,4-thiadiazole-3-one and
5-amino-3H-1 ,3,4-thiadiazole-2-one are the analogs of cytosine. In our first project, the
preparation of six thiadiazole nucleoside analogs is reported: 5-diacetylamino-1 ,2,4-
thiadiazol-3-one (1), 5-amino-2-(tetrahydrofuran-2-yl)-1 ,2,4-thiadiazol-3-one (2), 5-
amino-3-((2' -hydroxyethoxy)methyl)-1 ,3,4-thiadiazol-2-one (3), 5-amino-3-( 4' -hydroxy-
2' -hydroxyrnethyl-butyl)-1 ,3,4-thiadiazole-2-thione ( 4), (R)-5-am ino-3-(2' ,3' -
dihydroxypropyl)-1 ,3,4-thiadiazole-2-thione (5), and (S)-5-amino-3-(2' ,3 ' -
dihydroxypropyl )-1 ,3,4-thiadiazole-2-thione (6). (R)-5-amino-3-(2' ,3' -dihydroxypropyl)-1,3,4-thiadiazole-2-thione (5) and (S)-5-amino-3-(2' ,3' -dihydroxypropyl)-1 ,3,4-
thiadiazole-2-thione (6) are stereoisomers. Their racemic mixture 7 was also prepared and
tested. The synthesis, characterization, and properties of these new synthesized
thiadiazole derivatives are discussed. A dimerization of 5-amino-3H-1 ,3 ,4-thiadiazole-2-
thione (18) to produce di-(5-amino-1 ,3,4-thiadiazol-2-yl) disulfide (23) by sodium nitrite
with either acetic acid or stannic chloride is also reported. Preliminary results indicate
that 3 and 23 possess antimicrobial activity. In the second project, the synthesis of three series of bis-aminochloropyrimidine
derivatives with different types of linkers as potential DNA intercalators is described.
The first series are aminochloropyrimidines bridged by polyrnethylene chain linkers with
various lengths. The second series are bridged by polyether linkers to lower the
lipophilicity. The third series are bridged by linkers containing benzene rings to limit the
flexibility. The spectral data and other physical properties of the new compounds are
discussed. The preliminary screening results indicate that many new synthesized bisintercalators
are biologically active. The relationship between bioactivity and structure is
discussed as well.