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The synthesis and biological activities of seco C-9,11,21-trisnor-17-methyl-1 alpha,25-dihydroxyvitamin D(3) analogues (D-ring analogues) are described.

14,20-Bis-epi-1α,25-dihydroxy-19-norvitamin D3 and side chain analogues thereof have been synthesised via the 14,20-bis-epi-Inhoffen–Lythgoe diol 9. The synthesis of this precursor was performed via degradation of vitamin D2 and by total synthesis starting from Hajos–Wiechert ketone 24.

Vitamin D analogues, characterized by the absence of a D-ring (C-ring analogues) are described.

19-Nor-1 α,25-dihydroxyvitamin D 3 ( 2 ) was synthesized from A-ring precursor 5 and ketone 4 . Two synthesis of 5 were studied; one starting from (-)-quinic acid as a template and one starting from cis-1,3,5-cyclohexanetriol via a chemoenzymatic approach.

19-Nor-1 α,25-dihydroxyvitamin D 3 ( 2 ) was synthesized from A-ring precursor 5 and ketone 4 . Two synthesis of 5 were studied; one starting from (-)-quinic acid as a template and one starting from cis-1,3,5-cyclohexanetriol via a chemoenzymatic approach.

14,20-Bis-epi-1α,25-dihydroxy-19-norvitamin D3 and side chain analogues thereof have been synthesised via the 14,20-bis-epi-Inhoffen–Lythgoe diol 9. The synthesis of this precursor was performed via degradation of vitamin D2 and by total synthesis starting from Hajos–Wiechert ketone 24.

The synthesis and biological activities of seco C-9,11,21-trisnor-17-methyl-1 alpha,25-dihydroxyvitamin D(3) analogues (D-ring analogues) are described.

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 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 1alpha,25(OH)2D3 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.