SYNTHESIS AND BIOLOGICAL-ACTIVITY OF UNSYMMETRICAL BIS-STEROIDAL PYRAZINES RELATED TO THE CYTOTOXIC MARINE NATURAL PRODUCT CEPHALOSTATIN-1

A mild, high-yielding synthesis of symmetrical steroidal pyrazines was achieved from the dimerization of 2-amino-3-ketosteroids, which were produced in situ from the triphenylphosphine-water reduction of the corresponding alpha-azido ketone. 2-Azidocholestan-3-one gave the dimeric steroidal pyrazine very cleanly, and two known dimeric pyrazines based on androstanone were also made using this methodology. Both C-2-symmetric geometric isomers of the dimeric steroidal pyrazine derived from cholestane were prepared by reaction of 2,3-diaminocholestane with cholestane-2,3-dione. A route to unsymmetrical bis-steroidal pyrazines was based on the observation that alpha-acetoxy ketones react with alpha-amino oximes directly with no need for oxidation of intermediate dihydropyrazines. Heating either 2 beta,17 beta-dihydroxyandrostan-3-one diacetate or 2 beta,17 beta-dihydroxyhecogenin-3-one diacetate with 2-amino-3-methoxyiminocholestane in toluene at 145 degrees C gave the corresponding unsymmetrical pyrazine in moderate yield. Five of the steroidal pyrazines were evaluated in the National Cancer Institute's new in vitro, disease-oriented antitumor screen, but none showed sufficient activity to warrant in vivo investigation.