2,2-Functionalized analogues of 1alpha,25-dihydroxyvitamin D3, the potent inducers of cell differentiation

The Journal of Steroid Biochemistry and Molecular Biology
T FujishimaHiroaki Takayama

Abstract

All four possible A-ring stereoisomers of 2,2-dimethyl-1,25-dihydroxyvitamin D(3) (4) were designed and convergently synthesized. Nine-step conversion of methyl hydroxypivalate 6 provided the desired A-ring enyne synthon (13a,b) in good overall yield. Cross-coupling reaction of the A-ring synthon 13a,b with the CD-ring portion in the presence of palladium catalyst, followed by deprotection, gave the vitamin analogues (4a-d). We also synthesized four stereoisomers of 2,2-ethano-1,25-dihydroxyvitamin D(3) (5), as novel spiro-ring analogues having cyclopropane fused at the C2 position. Biological potencies of the synthesized compounds were assessed in terms of the vitamin D receptor (VDR) binding affinity, as well as the HL-60 cell differentiation-inducing activity. The 2,2-ethano analogue 5a showed a comparable activity to the natural hormone 1, while the 2,2-dimethyl analogue 4a exhibited one-third of the activity of 1 in cell differentiation, with the reduced VDR binding affinity.

References

Jun 8, 2000·Bioorganic & Medicinal Chemistry Letters·Y SuharaH Takayama

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Citations

Jan 4, 2007·Journal of Women's Health·Andrea L SikonAngelo A Licata
May 24, 2007·Rejuvenation Research·R Douglas ShytlePaula C Bickford
Aug 22, 2007·Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre·Byung Yong KangKang Oh Lee
Apr 9, 2011·Annals of Nutrition & Metabolism·S MuldowneyM Kiely
Dec 23, 2011·American Journal of Nephrology·Aida LydiaYasuhiko Tomino
Nov 23, 2012·American Journal of Nephrology·Liesbeth ViaeneChantal Mathieu
Feb 3, 2006·Natural Product Reports·James R Hanson
Mar 1, 2006·Expert Review of Endocrinology & Metabolism·Moray J Campbell, S Asad Abedin
Aug 27, 2013·Expert Review of Clinical Immunology·Arturo Borzutzky, Carlos A Camargo

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