Biochemical Significance of the 6‐s‐cis Conformation of the Steroid Hormone lα,25‐Dihydroxyvitamin D₃ Based on the Provitamin D Skeletona

Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1α,25-dihydroxyvitamin D analogsElectronic supplementary information (ESI) available: Further experimental details. See http://www.rsc.org/suppdata/ob/b2/b209147j/

“…68 Whereas the more stable extended transoid geometry has been shown experimentally to be involved in the binding in the LBD of the n-VDR, 11 the compact steroid-like cisoid geometry would be involved in the binding to the m-VDR. 69 Studies involving the biological evaluation of analogs locked into the s-cis geometry have substantiated this model. 70 Pre-1,25-D 3 (3at) is unique since it can be considered as a tautomer of 1,25-D 3 in the cisoid conformation.…”

6-s-cis Locked Analogues of the Steroid Hormone 1α,25-Dihydroxyvitamin D3. Synthesis of Novel A-Ring Stereoisomeric 1,25-Dihydroxy-3-epi-19-nor-previtamin D3 Derivatives

“…Pure pre-1α,25 standing in solution rearranges to 1α,25 with a half-life of 13.5 h at 37 °C, whereas when the C-19 methyl group is deuterated, rearrangement proceeds with a half-life of 81 h. However, whereas 1α,25 is significantly more active than pre-1α,25 (in a pentadeuterated form) 6 in assays reflecting genomic responses, the latter was equally as active as 1α,25 in assays for measuring nongenomic effects . Thus, 6- s - cis -1α,25 ( 1 ‘) was proposed as the active conformer in eliciting nongenomic effects, with pre-1α,25 ( 2 ) simply behaving as an excellent analogue of this conformer . 1α,25-(OH) 2 -Lumisterol ( 3 , Chart ), a 6- s - cis analogue, has been established to be equally active in eliciting the nongenomic activity of transcaltachia as both pre-1α,25 and 1α,25.…”

Synthesis and NMR Studies of 13C-Labeled Vitamin D Metabolites1

“…The seco-steroid vitamin D in its principal metabolic forms [Scheme : vitamin D 3 ( 1 , D3), 25-hydroxyvitamin D 3 ( 2 , 25-D3) and the hormonally active form 1α,25-dihydroxyvitamin D 3 ( 3 , 1,25-D3)] involve association with a variety of host systems including membranes and proteins during the course of mediating their biological actions. To gain insight into ligand design, extensive effort has gone into solid-state, solution, and computational studies of vitamin D ligands ( 1 − 3 ). 2b,− X-ray crystallographic results for a number of vitamin D structures including 1 − 3 reveal that the Δ 5,7 -diene is 6-s-trans and that this diene subunit deviates from planarity within a range of only ±8.1°. 2b, For crystalline 3 , the deviation from planarity is less than 3° 8c. The Δ 10(19) double bond deviates from the Δ 5,7 -diene plane, however, wherein the 5,10-s-cis bond deviates from planarity within the range ±52.3° 2b.…”

“…However, on the basis of the recent protein X-ray result, the Moras group has logically suggested 3a that the inability of 8 to bind to the n-VDR is that 8 is unable to twist (by 30°) about its 6,7-single bond because of the presence of the double bond. It is clear that there is a 360° continuum of topologies available to the hormone 1,25-D3 by rotation about its 6,7-single bond . Determination of the topology of 1,25-D3 as well as the other metabolites shown in Scheme by 6,7-single bond rotation in the active site of protein would provide insight into drug design.…”