Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0265264 (HOS)
 1,119 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1alpha,25-Dihydroxyvitamin D(3) (1) regulates a variety of biological actions through vitamin D receptor (VDR), including calcium and phosphorus homeostasis, bone remodeling, cellular proliferation and differentiation and many other functions. To enhance its potency and to study the structure/function relationship, we synthesized a series of analogs of 1 with a modification at the C-2alpha position. Introducing 2alpha-methyl, 2alpha-(3-hydroxypropyl), or 2alpha-(3-hydroxypropoxy) group increased its binding affinity for the VDR 2- to 4-fold compared to 1. The crystal structures of the VDR bound to these analogs provide a molecular explanation for the interaction between the 2alpha-substituents and water molecules exist in the VDR-ligand binding domain. Based on the accumulated knowledge in VDR agonists, we synthesized 2-substituted analogs of 'double side chain' (gemini), 19-norvitamin D(3) (MART-10), TEI-9647 (VDR antagonist), 1-alkylated vitamin D(3), 14-epi-previtamin D(3) etc. Gemini analogs showed potent HL-60 cell differentiation activity (13-38 times compared to 1), and MART-10 exhibited remarkable antiproliferative activity on PZ-HPV-7 cells even at 10(-10) M. (24S)-2alpha-(3-Hydroxypropoxy)-24-propyl-TEI-9647 showed potent VDR antagonism, and its IC(50) value was 7.4 pM against 10 nM of 1. 1alpha-Methyl-2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) improved the binding affinity for the mutant VDR(Arg274Leu), which causes hereditary vitamin D resistant rickets. 1alpha,25-Dihydroxy-2alpha-methyl-14-epi-previtamin D(3) showed moderate osteocalcin transcriptional activity on HOS cells. We theorize that modification at A-ring alone and in combination with functionalization of the other parts of the vitamin D molecule would provide important new information on the mechanism of vitamin D actions that could lead to the development of new therapeutic regimes for the treatment of various diseases.
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PMID:Structural refinement of seco-steroidal skeleton and the biological activity through nuclear receptors. 1875 37

The 14-epimer of MART-10, namely 14-epi-MART-10 (14-epi-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40% yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2alpha and 2beta were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2alpha or 2beta) was determined by 1H NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3).
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PMID:Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: implications for cancer and osteoporosis treatment. 1966 49