title: Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D3 analogues monohydroxylated in the A-ring.
abstract: The 20R- and 20S-isomers of 25-hydroxy-2-methylene-vitamin D3 and 3-desoxy-1α,25-dihydroxy-2-methylene-vitamin D3 have been synthesized. Two alternative synthetic routes were devised for preparation of the required A-ring synthons, starting from the chiral compound derived from the (-)-quinic acid and, alternatively, from the commercially available achiral precursor, monoprotected 1,4-cyclohexanedione. The A-ring dienynes were coupled by the Sonogashira process with the respective C,D-ring fragments, the enol triflates derived from the protected (20R)- or (20S)-25-hydroxy Grundmann ketones. All four compounds possessed significant in vivo activity on bone calcium mobilization and intestinal calcium transport. The presence of a 2-methylene group increased intestinal calcium transport activity of all four analogues above that of the native hormone, 1α,25-dihydroxyvitamin D3. In contrast, bone calcium mobilization was equal to that produced by 1α,25-dihydroxyvitamin D3 in compounds having a (20S)-configuration or diminished to one-tenth that of 1α,25-dihydroxyvitamin D3 in compounds with a (20R)-configuration.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: Izabela K
authors.initials: IK
authors.lastname: Sibilska
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ochalek
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002112:Calcifediol / Q000737:chemistry* / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000737:chemistry; D002118:Calcium / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C468519:2-methylene-1,25-dihydroxy-19-norvitamin D3; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol; D002118:Calcium