Total synthesis of 25-Hydroxy-16,23E-diene Vitamin D3 and 1α,25-Dihydroxy-16,23E-diene Vitamin D3: separation of genomic and nongenomic vitamin D Activities

Low-Calcemic, Highly Antiproliferative, 1-Difluoromethyl Hybrid Analogs of the Natural Hormone 1α,25-Dihydroxyvitamin D3: Design, Synthesis, and Preliminary Biological Evaluation

“…Chemistry: Syntheses of hybrid analogs 6 and 7 are outlined in Scheme 1, starting with the recently reported A-ring 1-CHF 2 7-phosphine oxide synthon (()-8. 17 Lythgoe-type coupling 18 of racemic phosphine oxide 8 with enantiomerically pure C,Dring C-8 ketone 9 led smoothly after desilylation to a mixture of diastereomers from which the major diasteromer analog (+)-6 was isolated via preparative HPLC. Similarly, coupling with C,D-ring C-8 ketone 10 led easily after desilylation and HPLC purification to analog (-)-7.…”

Conceptually New Low-Calcemic Oxime Analogues of the Hormone 1α,25-Dihydroxyvitamin D3: Synthesis and Biological Testing

“…Before such coupling, installing the O-methyl oxime group into the C,D-ring side chain tert-butyl ketone 6 proceeded smoothly to give exclusively the (E)oxime methyl ether 7 (stereochemical assignment based on 13 C nuclear magnetic resonance (NMR) spectroscopy), 30 due presumably to the strongly unfavorable steric congestion that would be present in the corresponding (Z)-oxime methyl ether. 30 Horner-Wadsworth-Emmons (HWE) coupling 6 racemic A-ring phosphine oxide 9 31 produced, after desilylation, calcitriol O-methyl oxime analogues 4 as two diastereomers, with enantiomerically pure diastereomer 4b of natural A-ring stereochemistry predominating. As we have done generally before, 8,31 tentative assignment of the A-ring stereochemistry in analogues 4 was achieved based on characteristic 1 H NMR peaks and optical rotations (Table 1).…”

“…Many analogues of the hormone 1α,25-dihydroxyvitamin D 3 (calcitriol, 1 ) have been synthesized . Several of these analogues currently are being evaluated as drug candidates for cancer chemoprevention and chemotherapy as well as for chemotherapy of other human diseases such as osteoporosis, psoriasis, and immune system disorders. , Successful drugs must have an acceptable therapeutic index, with a good separation between efficacy and toxicity (e.g., hypercalcemia) and desirable pharmacological properties (e.g., high metabolic stability). , Because the main sites of catabolism are located in the C,D-ring side chain of calcitriol ( 1 ), analogues with catabolism-blocking side chain olefinic − and acetylenic unsaturation, including side chain keto versions, , have been developed. No side chain oxime analogues, however, have been reported.…”

“…4,5 Successful drugs must have an acceptable therapeutic index, with a good separation between efficacy and toxicity (e.g., hypercalcemia) and desirable pharmacological properties (e.g., high metabolic stability). 4,5 Because the main sites of catabolism are located in the C,D-ring side chain of calcitriol (1), 1 analogues with catabolism-blocking side chain olefinic [6][7][8] and acetylenic 9 unsaturation, including side chain keto versions, 10,11 have been developed. No side chain oxime analogues, however, have been reported.…”

Chemical Reactivity of Ro-26-9228, 1α-Fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol in Aqueous Solution

“…Because many different cell types have receptors for vitamin D 3 and its metabolites, modifications of its structure have been explored in an attempt to add specificity to its actions [1][2][3] which has resulted in therapeutic agents for indications such as psoriasis (calcipotriol), secondary hyperparathyroidism [19-nor-1,25(OH)2D2], and reduction of elevated parathyroid hormone (doxercalciferol). 4 Screening studies showed that a fluorinated vitamin D 3 analog Ro-26-9228 (1a-fluoro-25hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol), 2, increased the bone mineral density but showed reduced calcemia compared with calcitriol in rats and humans.…”