Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor

2014 ◽  
Vol 57 (10) ◽  
pp. 4073-4087 ◽  
Author(s):  
Takeru Kudo ◽  
Michiyasu Ishizawa ◽  
Kazuki Maekawa ◽  
Makoto Nakabayashi ◽  
Yusuke Watarai ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Triple Bond ◽  
Side Chain ◽  
Partial Agonists

The First Locked Side-Chain Analogues of Calcitriol (1α,25-Dihydroxyvitamin D3) Induce Vitamin D Receptor Transcriptional Activity

2003 ◽  
Vol 5 (22) ◽  
pp. 4033-4036 ◽  
Author(s):  
Xenxo Pérez-García ◽  
Antonio Rumbo ◽  
María Jesús Larriba ◽  
Paloma Ordóñez ◽  
Alberto Muñoz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Transcriptional Activity ◽  
Side Chain ◽  
Dihydroxyvitamin D3

scholarly journals Carborane-based design of a potent vitamin D receptor agonist

2016 ◽  
Vol 7 (2) ◽  
pp. 1033-1037 ◽  
Author(s):  
Rocio Otero ◽  
Samuel Seoane ◽  
Rita Sigüeiro ◽  
Anna Y. Belorusova ◽  
Miguel A. Maestro ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Agonist ◽  
Side Chain ◽  
Vitamin D Analog ◽  
Dihydrogen Bonding

The development of a promising clinical antitumor vitamin D analog possessing a side-chain o-carborane cluster that efficiently binds to VDR by unconventional dihydrogen bonding (BH⋯HN) is described.

Design, Synthesis and Evaluation of Side-Chain Hydroxylated Derivatives of Lithocholic Acid as Potent Agonists of the Vitamin D Receptor (VDR)

2021 ◽  
pp. 105202
Author(s):  
Carmen M. González ◽  
Sunil Gaikwad ◽  
Gonzalo Lasanta ◽  
Julian Loureiro ◽  
Niclas Nilsson ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Side Chain ◽  
Design Synthesis ◽  
Derivatives Of

Potent Antagonist for the Vitamin D Receptor: Vitamin D Analogues with Simple Side Chain Structure

2010 ◽  
Vol 53 (15) ◽  
pp. 5813-5826 ◽  
Author(s):  
Yuta Sakamaki ◽  
Yuka Inaba ◽  
Nobuko Yoshimoto ◽  
Keiko Yamamoto
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Chain Structure ◽  
Side Chain ◽  
Vitamin D Analogues ◽  
Potent Antagonist

scholarly journals Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

2018 ◽  
Vol 19 (9) ◽  
pp. 2583 ◽  
Author(s):  
Tomasz Wasiewicz ◽  
Anna Piotrowska ◽  
Justyna Wierzbicka ◽  
Andrzej Slominski ◽  
Michal Zmijewski
Keyword(s):  
Vitamin D ◽  
Cell Lines ◽  
Vitamin D Receptor ◽  
Melanoma Cell ◽  
Human Melanoma ◽  
Side Chain ◽  
Short Side ◽  
Vitamin D Analogs ◽  
Splicing Variants ◽  
Melanoma Cell Lines

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D—21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)2D3 and 25(OH)D3, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)2D3 and became VDR−/−CYP27B1−/−). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog—21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)2D3, 25(OH)D3 and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR−/−. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.

scholarly journals Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor

2003 ◽  
Vol 17 (10) ◽  
pp. 2028-2038 ◽  
Author(s):  
Manuel Macias Gonzalez ◽  
Petra Samenfeld ◽  
Mikael Peräkylä ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Inverse Agonist ◽  
Side Chain ◽  
Vitamin D Analog

scholarly journals Convergent synthesis and biological evaluation of vitamin D analogues as potential anticancer agents

2016 ◽  
Author(s):  
Andrzej Kutner
Keyword(s):  
Colon Cancer ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Anticancer Agents ◽  
Biological Evaluation ◽  
Side Chain ◽  
Synthesis And Biological Evaluation ◽  
Ht 29

Synthetic analogs of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2D3] and 1alpha,25-dihydroxyergocalciferol [1alpha,25-(OH)2D2] have long been considered as key regulators of calcium and phosphate homeostasis. These analogs have been recently investigated as potential therapeutics against a number of pathological states, including metabolic, dermatological, immune and hyperproliferative diseases. Analogues of 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, modified in the cyclohexane A-ring and in the aliphatic side-chain, potentiated the efficiency of cytostatics and/or cooperated efficiently with polyphenol in human myeloid leukemia cells (HL60, U937 and MOLM-13) and in several animal models of leukemias and solid tumours. The therapeutic effect resulted from the thorough combination of several key factors, including the selection of vitamin D-sensitive cancer model, type of cytostatic, the right scheme and route of administration of both therapeutics, correlation with vitamin D receptor level and managing of the hypercalcemic side effect of vitamin D. In this work our synthesis and biological evaluation is outlined of a novel generation of vitamin D analogs as well as our investigation of their anticancer profile in vitro and in vivo. Our convergent synthesis started from vitamin D-like advanced intermediates and separately prepared side-chain fragments. This way, in an over twenty-step syntheses, a series of analogs were obtained containing, compared to the parent vitamin D hormones, 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, an additional chiral center or conjugated diene system in the side-chain and/or modified 5,6-trans or 19-nor A-ring. Some of the new analogs, pre-selected in a number of in vitro models, showed, in the combined treatment with cytostatics, the beneficial activity profile in both, murine colon cancer MC38 and in human colon cancer HT-29 cells. Our analogues also modulated expression of genes related to stem-like phenotype in vitamin D receptor (VDR) positive colon cancer cells, HT-29 and HCT-116, at different differentiation states, undergoing renewal after the treatment with 5-FU. The analogs induced differentiation of VDR positive A375 and VDR negative SK-MEL 188b human melanoma cells. Some of our analogs also displayed moderate cytotoxic and pro-apoptotic activity in diffuse large B-cell lymphoma (DLBCL) and concentration and time-dependent antiproliferative action upon stimulated B-cells from healthy donors. Data available from the protein data bank were used for the rational design of the next generation of analogs by minimizing the electrostatic interaction energies, after the reconstruction of a charge densities using pseudoatom databank. Due to a low calcemic activity and anticancer profile in vivo, selected new analogues might be considered as promising candidates for further preclinical evaluation as potential anticancer agents.

scholarly journals Convergent synthesis and biological evaluation of vitamin D analogues as potential anticancer agents

2016 ◽  
Author(s):  
Andrzej Kutner
Keyword(s):  
Colon Cancer ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Anticancer Agents ◽  
Biological Evaluation ◽  
Side Chain ◽  
Synthesis And Biological Evaluation ◽  
Ht 29

Synthetic analogs of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2D3] and 1alpha,25-dihydroxyergocalciferol [1alpha,25-(OH)2D2] have long been considered as key regulators of calcium and phosphate homeostasis. These analogs have been recently investigated as potential therapeutics against a number of pathological states, including metabolic, dermatological, immune and hyperproliferative diseases. Analogues of 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, modified in the cyclohexane A-ring and in the aliphatic side-chain, potentiated the efficiency of cytostatics and/or cooperated efficiently with polyphenol in human myeloid leukemia cells (HL60, U937 and MOLM-13) and in several animal models of leukemias and solid tumours. The therapeutic effect resulted from the thorough combination of several key factors, including the selection of vitamin D-sensitive cancer model, type of cytostatic, the right scheme and route of administration of both therapeutics, correlation with vitamin D receptor level and managing of the hypercalcemic side effect of vitamin D. In this work our synthesis and biological evaluation is outlined of a novel generation of vitamin D analogs as well as our investigation of their anticancer profile in vitro and in vivo. Our convergent synthesis started from vitamin D-like advanced intermediates and separately prepared side-chain fragments. This way, in an over twenty-step syntheses, a series of analogs were obtained containing, compared to the parent vitamin D hormones, 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, an additional chiral center or conjugated diene system in the side-chain and/or modified 5,6-trans or 19-nor A-ring. Some of the new analogs, pre-selected in a number of in vitro models, showed, in the combined treatment with cytostatics, the beneficial activity profile in both, murine colon cancer MC38 and in human colon cancer HT-29 cells. Our analogues also modulated expression of genes related to stem-like phenotype in vitamin D receptor (VDR) positive colon cancer cells, HT-29 and HCT-116, at different differentiation states, undergoing renewal after the treatment with 5-FU. The analogs induced differentiation of VDR positive A375 and VDR negative SK-MEL 188b human melanoma cells. Some of our analogs also displayed moderate cytotoxic and pro-apoptotic activity in diffuse large B-cell lymphoma (DLBCL) and concentration and time-dependent antiproliferative action upon stimulated B-cells from healthy donors. Data available from the protein data bank were used for the rational design of the next generation of analogs by minimizing the electrostatic interaction energies, after the reconstruction of a charge densities using pseudoatom databank. Due to a low calcemic activity and anticancer profile in vivo, selected new analogues might be considered as promising candidates for further preclinical evaluation as potential anticancer agents.

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