Noncalcemic, Antiproliferative, Transcriptionally Active, 24-Fluorinated Hybrid Analogues of the Hormone 1α,25-Dihydroxyvitamin D3. Synthesis and Preliminary Biological Evaluation
- 1 July 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (16) , 3008-3014
- https://doi.org/10.1021/jm980031t
Abstract
Four new hybrid analogues of 1α,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 1β,3α-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.Keywords
This publication has 16 references indexed in Scilit:
- Antiproliferative Hybrid Analogs of the Hormone 1α,25-Dihydroxyvitamin D3: Design, Synthesis, and Preliminary Biological EvaluationThe Journal of Organic Chemistry, 1997
- Synthesis of CD-ring modified 1α,25-dihydroxy vitamin D analogues: Five-membered D-ring analoguesBioorganic & Medicinal Chemistry Letters, 1997
- Synthesis and Biological Activity of 1α,25-Dihydroxy-18-norvitamin D3 and 1α,25-Dihydroxy-18,19-dinorvitamin D3Journal of Medicinal Chemistry, 1996
- 1α,25-Dihydroxyvitamin D3 Hybrid Analogs with Structural changes at both the A-ring and the C,D-ring side-chain. IIBioorganic & Medicinal Chemistry Letters, 1995
- 2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3. Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological TestingThe Journal of Organic Chemistry, 1995
- 1α,25-dihydroxyvitamin D3 hybrid analogs with structural changes at both the A-ring and the C,D-ring side-chainBioorganic & Medicinal Chemistry Letters, 1994
- Direct Injection Method for Quantitation of .DELTA.-Aminolevulinic Acid in Urine by High-Performance Liquid Chromatography.CHEMICAL & PHARMACEUTICAL BULLETIN, 1992
- Studies of vitamin D (calciferol) and its analogs. 39. Arocalciferols: synthesis and biological evaluation of aromatic side-chain analogs of 1.alpha.,25-dihydroxyvitamin D3Journal of Medicinal Chemistry, 1991
- Antitumor properties of tetrahydrobenz(a)anthraquinone derivativesJournal of Medicinal Chemistry, 1990
- Determination of biological activity of 24,24-difluoro-1,25-dihydroxyvitamin D3 in the chick using a new method for assessing intestinal calcium uptakeArchives of Biochemistry and Biophysics, 1982