Synthesis and biological evaluation of 6-methyl analog of 1alpha,25-dihydroxyvitamin D3.
Among more than 3000 analogs of 1alpha,25-dihydroxyvitamin D3 synthesized to date, only a few were characterized by structural modifications in the seco-B-ring. The compounds alkylated at C-6 seemed to be interesting targets for synthetic efforts. Such vitamin D analogs easily undergo thermal conversion to their previtamin forms. The results of molecular modeling indicate that significant deviation from planarity must be present in their molecules associated with the interaction of the 6-alkyl substituent and hydrogens from the C-ring. The synthesis of the analog of 1alpha,25-(OH)2D3, being characterized by the presence of the 6-methyl group, is reported here, together with the results of preliminary testing of its biological potency. This 6-alkylated compound was efficiently prepared using a novel stereoconvergent strategy in which the ring A and the triene unit of the vitamin D skeleton are constructed by a one-pot Pd-catalyzed tandem cyclization-Negishi coupling process.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Katarzyna
K
Sokolowska
Antonio
A
Mouriño
Rafal R
RR
Sicinski
Rita
R
Sigüeiro
Lori A
LA
Plum
Hector F
HF
DeLuca
D000818:Animals; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D008956:Models, Chemical; D010165:Palladium / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry
C552202:1,25-dihydroxy-6-methylvitamin D3; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D010165:Palladium; D002117:Calcitriol