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The Biological Activity of Nonsteroidal Vitamin D Hormone Analogs Lacking Both the C‐ and D‐Rings
Author(s) -
Verstuyf Annemieke,
Verlinden Lieve,
Van Baelen Hugo,
Sabbe Katrien,
D'Hallewyn Chris,
De Clercq Pierre,
Vandewalle Maurits,
Bouillon Roger
Publication year - 1998
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.1998.13.4.549
Subject(s) - side chain , biological activity , chemistry , stereochemistry , vitamin d and neurology , in vitro , potency , in vivo , ring (chemistry) , biochemistry , endocrinology , biology , microbiology and biotechnology , organic chemistry , polymer
1α,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‐methylenecyclohexane‐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 1α,25(OH) 2 D 3 has between 10 and 30% of the biological activity of 1α,25(OH) 2 D 3 when tested in vitro (prodifferentiating effects on HL‐60 and MG‐63; antiproliferating activity on MCF‐7 and keratinocytes) but has minimal in vivo calcemic effects. Introduction of several side chain modifications created analogs with increased intrinsic noncalcemic biological properties, whereas their calcemic potency remains very low. These data demonstrate that the full CD‐rings are not mandatory for the biological activity of 1α,25(OH) 2 D 3 since they can be replaced by a new ring structure which generates an appropriate spacing of the A‐seco B‐rings in relation to the side chain. The biological activity of these nonsteroidal analogs probably involves a classical genomic activation since they are also active in transfection assays using an osteocalcin vitamin D responsive element coupled to a human growth hormone reporter gene.