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.
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.
G H
GH
Posner
J K
JK
Lee
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Q
Wang
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S
Peleg
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M
Burke
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H
Brem
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P
Dolan
T W
TW
Kensler
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