The synthesis and reactivity of 3 beta-(2-alkynylsulfonyl)- and 3 beta-(2-alkynylsulfonylmethyl) androst-5-en-17-ones as inhibitors of glucose-6-phosphate dehydrogenase.
3 beta-(Hexadec-2-ynylsulfonyl)androst-5-en-17-one, 2c, was designed as an analog of dehydroepiandrosterone sulfatide 1c, a potent, natural inhibitor of glucose-6-phosphate dehydrogenase (G6PDH). Nucleophilic substitution of 1-bromo hexadec-2-yne 11 with 3 beta-mercaptoandrost-5-en-17-one followed by oxidation afforded 2c. The propargylic sulfone 2c may tautomerize to the electrophilic allenic sulfone 3a and thus function as a masked affinity label of the steroidal binding site of G6PDH. Since 2c demonstrated low potency as an inhibitor of G6PDH, a sulfonylmethyl analog 4b was also designed and synthesized. Synthesis of 4b began by methylenation of androst-5-en-3,17-dione 17-ketal 6 with the Tebbe reagent, to yield the 3-methyleneandrost-5-ene 7. Hydroboration, followed by oxidation, gave a mixture of 3 alpha- and 3 beta-hydroxymethyl isomers 8a and 8b, respectively. The 3 beta alcohol 8b was converted to the thiol 10. Alkylation of 10 with 1-bromo-2-hexadecyne 11, followed by selective oxidation, gave the desired acetylenic sulfone 4b. Insertion of the methylene in 4a and 4b significantly increased their G6PDH inhibitory properties over the initial compounds, 2b and 2c.
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122-2585, USA.
J R
JR
Williams
J C
JC
Boehm
D000495:Allosteric Site; D000736:Androstenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C097467:3-(hexadec-2-ynylsulfonylmethyl)androst-5-en-17-one; D000736:Androstenes; D004791:Enzyme Inhibitors; D005954:Glucosephosphate Dehydrogenase