Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha, 25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation.
Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with 1beta, 3alpha-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.
Posner
G H
GH
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, Department of Medical Specialities, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lee
J K
JK
Wang
Q
Q
Peleg
S
S
Burke
M
M
Brem
H
H
Dolan
P
P
Kensler
T W
TW
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000652:urine*; D002455:Cell Division / Q000187:drug effects; D002942:Circular Dichroism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase
D000970:Antineoplastic Agents; C113642:JK 1624F2-1; C113641:QW 1624F2-1; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium