The biological activity of nonsteroidal vitamin D hormone analogs lacking both the C- and D-rings

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Annemieke VerstuyfR Bouillon

Abstract

1alpha,25-dihydroxyvitamin D is a key calcium-regulating hormone but also displays potent differentiating and antiproliferative activities on many cell types. The structural requirements of this secosteroid hormone have been extensively studied for the A-ring and side chain, whereas relatively little is known about the requirements of the natural CD-ring structure for the vitamin D-like biological activity. We have embarked on a vast program in which derivatives were synthesized and evaluated characterized by profound structural changes in the central C/D-region. This first series of nonsteroidal analogs consists of (1R,3S)-5-((Z,2E)-4-((1S,3S)-3-(4-hydroxy-4-methylpentyl)-1,2,2-++ +trimethylcyclopentyl)-2-butenylidene)-4-methylenecyclohexan e-1,3-diol (KS 176) and derivatives thereof. These analogs are characterized by the absence of normal C- and D-rings and by the presence of an unnatural five-membered ring which we call the E-ring. KS 176 with the otherwise natural side chain structure of 1alpha,25(OH)2D3 has between 10 and 30% of the biological activity of 1alpha,25(OH)2D3 when tested in vitro (prodifferentiating effects on HL-60 and MG-63; antiproliferating activity on MCF-7 and keratinocytes) but has minimal in vivo calc...Continue Reading

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Citations

Mar 7, 2000·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·A VerstuyfR Bouillon
Apr 24, 2001·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·L VerlindenR Bouillon
Jun 23, 2005·Diabetologia·C MathieuR Bouillon
Mar 4, 2009·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Garrett MinnePierre J De Clercq
Nov 4, 2000·Expert Opinion on Investigational Drugs·A VerstuyfC Mathieu
Mar 25, 2014·Expert Opinion on Therapeutic Patents·Narasimha Rao BollaAndrzej Kutner
Mar 28, 2012·Expert Opinion on Therapeutic Patents·Carsten CarlbergAntonio Mouriño
Jul 26, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Guy EelenAnnemieke Verstuyf
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Pierre J De ClercqRoger Bouillon
Apr 30, 2005·Molecular Endocrinology·Mikael PeräkyläCarsten Carlberg
Apr 16, 2005·The Journal of Biological Chemistry·Jo VanoevelenFrank Wuytack
Jun 1, 2002·Bioorganic & Medicinal Chemistry Letters·Yusheng WuAnnemieke Verstuyf
Jun 1, 2002·Bioorganic & Medicinal Chemistry Letters·Yusheng WuAnnemieke Verstuyf
Apr 7, 2007·Bioorganic & Medicinal Chemistry·Laura Sánchez-AbellaVicente Gotor

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