Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and biological evaluation.
New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.
Posner
G H
GH
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, USA. ghp@jhu.edu
Crawford
K
K
Siu-Caldera
M L
ML
Reddy
G S
GS
Sarabia
S F
SF
Feldman
D
D
van Etten
E
E
Mathieu
C
C
Gennaro
L
L
Vouros
P
P
Peleg
S
S
Dolan
P M
PM
Kensler
T W
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D018167:Receptors, Calcitriol; D013450:Sulfones; D002117:Calcitriol