title: Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds.
abstract: In an attempt to prepare vitamin D analogues that are superagonists, (20R)- and (20S)-isomers of 1α-hydroxy-2-methylenevitamin D3 and 1α,25-dihydroxy-2-methylenevitamin D3 have been synthesized. To prepare the desired A-ring dienyne fragment, two different approaches were used, both starting from the (-)-quinic acid. The obtained derivative was subsequently coupled with the C,D-ring enol triflates derived from the corresponding Grundmann ketones, using the Sonogashira reaction. Moreover, (20R)- and (20S)-1α,25-dihydroxy-2-methylenevitamin D3 compounds with an (5E)-configuration were prepared by iodine catalyzed isomerization. All four 2-methylene analogues of the native hormone were characterized by high in vitro activity. As expected, the 25-desoxy analogues were much less potent. Among the synthesized compounds, two of them, 1α,25-dihydroxy-2-methylenevitamin D3 and its C-20 epimer, were found to be almost as active as 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) on bone but more active in intestine.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Warsaw , Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Izabela K
authors.initials: IK
authors.lastname: Sibilska
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Warsaw , Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Szybinski
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Warsaw , Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004100:Dihydroxycholecalciferols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D042381:Granulocyte Precursor Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C519954:2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3; D004100:Dihydroxycholecalciferols; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium