Pharmaceutical chemistry

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.

Cephalostatin 1 has been isolated from the colonial marine worm Cephalodiscus gilchristi (Phylum Hemichordata) in the Indian Ocean. It has shown biomedical potential in preclinical trials as a cell growth inhibitor, active against U. S. murine P388 lymphocyte leukemia ED5010^-7-10^-9 μ/ml and a potent growth inhibitor against solid tumor types. Our research is focusing on developing methodology to produce disteroidal pyrazine and the introduction of delta 14, 15 unsaturation and C-16 hydroxyl groups in Cephalostatin 1A. The synthetic intermediates may be useful for biosynthetic studies and also analogues can be used to study structure-activity relationships.