Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation.
Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.
Peleg
Sara
S
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Petersen
Kimberly S
KS
Suh
Byung Chul
BC
Dolan
Patrick
P
Agoston
Elin S
ES
Kensler
Thomas W
TW
Posner
Gary H
GH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000652:urine; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; C517243:KSP-BCS-1alpha-CHF2-20-epi-22-oxa-bishomo-26-OH compound; C517242:KSP-BCS-1alphaCHF2-1624F2-2 compound; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium