20-EPI-vitamin D3 analogues: A novel class of potent regulators of cell growth and immune responses

Binderup, Lise; Latini, Scilla; Binderup, Ernst; Bretting, Claus; Calverley, Martin J.; Hansen, Kerrin

doi:10.1016/0006-2952(91)90426-6

Cited by 309 publications

(192 citation statements)

References 28 publications

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“…Because previous characterization of this particular group has suggested that their intrinsic binding affinities for VDR and DBP do not differ from those of the natural ligand (17,18), 20-epi compounds represent a class of compounds that might instead act by affecting VDR structure, which in turn would somehow lead to enhanced VDR function and biological activity. Previous studies using nuclear extracts prepared from ligand-treated cells indicated that 20-epi analogues at low concentrations have much stronger effects on VDR/RXR-DNA complex formation than 1,25(OH) 2 D 3 (19).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the DRIP complex strongly potentiated transcription mediated by VDR/RXR in a cell-free, ligand-dependent transcription assay on chromatin-assembled templates. These observations suggested that 1,25(OH) 2 (17). In addition, the presence of vitamin D binding protein (DBP) in culture has little effect on the biological activity of 1,25(OH) 2 D 3 or a 20-epi analogue, suggesting that the difference in cellular uptake of these ligand mediated by DBP is unlikely a major factor for the augmented activity of 20-epi compounds (18).…”

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confidence: 99%

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20-Epi Analogues of 1,25-Dihydroxyvitamin D3 Are Highly Potent Inducers of DRIP Coactivator Complex Binding to the Vitamin D3 Receptor

Yang¹,

Freedman

1999

Journal of Biological Chemistry

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1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) plays a major role in the stimulation of bone growth, mineralization, and intestinal calcium and phosphate absorption; it also acts as a general inhibitor of cellular proliferation. Several new, clinically relevant compounds dissociate antiproliferative and calcemic activities of 1,25(OH) 2 D 3 , but the molecular basis for this has not been clearly elucidated. Here, we tested whether the potency of one class of compounds, 20-epi analogues, to induce myeloid cell differentiation, is because of direct molecular effects on vitamin D receptor (VDR). We report that two 20-epi analogues, MC1627 and MC1288, induced differentiation and transcription of p21Waf1,Cip1 , a key VDR target gene involved in growth inhibition, at a concentration 100-fold lower than that of 1,25(OH) 2 D 3 . We compared this sensitivity to analogue effects on VDR interacting proteins: RXR, GRIP-1, and DRIP205, a subunit of the DRIP coactivator complex. Compared with the interaction of VDR with RXR or GRIP-1, the differentiation dose-response most closely correlated to the ligand-dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system. These results provide compelling links between the efficiency of the 20-epi analogue in inducing VDR/DRIP interactions, transactivation in vitro, and its enhanced ability to induce cellular differentiation.In the early part of this century, vitamin D 3 was discovered as a fat-soluble substance with antirachitic activity (1). It was subsequently found that vitamin D 3 must be metabolized to an active hormonal form before it can elicit its biological effects (2). Upon exposure to UV light, vitamin D 3 is synthesized, converted in the liver to 25-hydroxyvitamin D 3 , and hydroxylated in the kidney to its active form, 1,25-dihydroxyvitamin D3 (1,25(OH) 2 D 3 ).1 Functions of 1,25(OH) 2 D 3 include the stimulation of bone growth and mineralization and the increase intestinal calcium and phosphate absorption. In recent years, accumulating evidence points to the involvement of 1,25(OH) 2 D 3 in a number of diverse biological processes, including the regulation of cellular proliferation and differentiation, immunosuppression, and hormone secretion.Similar to other steroid hormones, 1,25(OH) 2 D 3 acts by binding stereospecifically to a high affinity, low capacity intracellular receptor protein, the vitamin D receptor (VDR) (3). VDR is a 48-kDa protein and is a member of the steroid/nuclear receptor superfamily that contains discrete functional domains for ligand binding, DNA binding, and transcriptional activation (4). Transactivation by 1,25(OH) 2 D 3 requires a carboxyl-terminal ␣-helical region, termed activation function-2 (AF-2), that forms part of the ligand-binding pocket (5). Upon binding to 1,25(OH) 2 D 3 , VDR dimerizes with the retinoid X receptor (RXR) to enable high affinity interactions with a specific vitamin D-responsive element (VDRE) located in 5Ј-flanking regions of target g...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

20-Epi Analogues of 1,25-Dihydroxyvitamin D3 Are Highly Potent Inducers of DRIP Coactivator Complex Binding to the Vitamin D3 Receptor

Yang¹,

Freedman

1999

Journal of Biological Chemistry

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“…To reduce the inactivating C-3 epimerization, the A-ring can be modified as the 19-nor variant, 9 or by changing the geometry of the 5E double bond; 10 as a result, biological activities are enhanced. 11,12 The discovery that 20-epi vitamin D analogs can exhibit higher potencies 13,14 engendered the synthesis of Gemini, distinguished by two identical side chains emanating at C-20. 15,16 In a second generation of Gemini compounds, chain-modifications aimed at metabolic retardation and enhanced differentiation were introduced stereoselectively 17,18 and their effects evaluated.…”

Section: Introductionmentioning

confidence: 99%

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Garay

Jankowski

Lizano

et al. 2007

Bioorganic & Medicinal Chemistry

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Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1α,25-dihydroxyvitamin D 3 (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1α,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less effciently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells.

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“…Similarly, Dilworth et al (1994) have shown that MC 1288 has five-times greater affinity for calf thymus VDR than calcitriol. Binderup et al (1991) have, however, reported that for chick intestinal VDR the 20-epi analogs have similar affinities to calcitriol. A recombinant VDR is not able to bind to human osteocalcin VDRE alone, but requires auxiliary factors, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The three calcitriol analogs examined in this study (KH 1060, MC 903, MC 1288 are all capable of inducing the biological effects of calcitriol, i.e. they inhibit cell proliferation and induce differentiation (Binderup and Bramm, 1988;Binderup et al, 1991). We have studied in more detail the effectr of the three analogs on the expression of two marker genes of the differentiated osteoblasts, namely alkaline phosphatase and osteocalcin, in the MG-63 cells.…”

Section: Discussionmentioning

confidence: 99%

Synthetic 20‐Epi Analogs of Calcitriol are Potent Inducers of Target‐Gene Activation in Osteoblastic Cells

Ryhänen¹,

Jääskeläinen²,

Mäenpää³

1996

European Journal of Biochemistry

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We have compared the actions of calcitriol and its three synthetic analogs, 20-epi-22-oxa-24a,26a,27a-trihomo-1 a,25-dihydroxyvitamin D, (KH 1060), 1 a,24S-(OH),-22-ene-26,27-cyclopropyl vitamin D, (MC 903) and 20-epi-la,25-dihydroxyvitamin D, (MC 1288), on the expression of two marker genes of differentiated osteoblasts, namely alkaline phosphatase and osteocalcin, using human MG-63 osteosarcoma cells. Calcitriol and the analogs had qualitatively similar stimulatory effects on target-gene activation. Quantitatively, MC 903 behaved in most experiments essentially as the parent compound calcitriol. In vitamin D receptor/DNA complex formation MC 903, however, was more potent than calcitriol. In contrast, the 20-epi analogs, KH 1060 and MC 1288, were much more potent even at lower concentrations, than calcitriol and MC 903 in stimulating alkaline phosphatase activity, osteocalcin mRNA synthesis and osteocalcin secretion. The stimulation occurred to a greater degree and for a longer period than with calcitriol. This effect was apparently mediated by stronger and longer lasting binding of the vitamin D receptor to the osteocalcin vitamin D responsive element by the 20-epi analogs. After a 6-h treatment and during subsequent culture without hormone, the effects of the 20-epi analogs were also stronger and lasted longer than'those with calcitriol or MC 903. Collectively, at comparable and lower concentrations, the 20-epi analogs, KH 1060 and MC 1288, mediate much stronger and longer lasting stimulatory effects than calcitriol or its analog MC 903 on target-gene expression associated with the differentiated phenotype of the MG-63 human osteosarcoma cells.Keywords: vitamin D; analog: receptor; osteocalcin.In addition to its role in calcium homeostasis, the hormone 1 a,25-dihydroxyvitamin D, (calcitriol) is involved in the regulation of processes such as cell differentiation and proliferation in normal and malignant cells (Pols et al., 1990;Suda et al., 1990). This discovery has led to renewed interest in developing new vitamin D analogs with decreased calcemic activity and with selectivity for a particular type of tissue or disease. The analogs are potentially useful in the treatment of several types of cancer and skin disorders (Bikle, 1992;Bouillon et al., 1995). A large number of vitamin D analogs have already been synthesized (Figadire et al., 1991 ;Bouillon et al., 1995) and several candidate analogs have shown promising therapeutic activity. Among the compounds, 1a,24S-(OH),-22-ene-26,27-cyclopropyl vitamin D, (MC 903 ; calcipotriol) has already been approved for clinical use as an antipsoriatic drug (Kragballe, 1989), and the 20-epi analogs, 20-epi-22-oxa-24a,26a,27a-trihomo-la,25-dihydroxyvitamin D, (KH 1060) and 20-epi-la,25-dihydroxyvitamin D, (MC 1288), have shown marked immunosuppressive activity (Bindemp et al., 1991).

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20-EPI-vitamin D3 analogues: A novel class of potent regulators of cell growth and immune responses

Cited by 309 publications

References 28 publications

20-Epi Analogues of 1,25-Dihydroxyvitamin D3 Are Highly Potent Inducers of DRIP Coactivator Complex Binding to the Vitamin D3 Receptor

20-Epi Analogues of 1,25-Dihydroxyvitamin D3 Are Highly Potent Inducers of DRIP Coactivator Complex Binding to the Vitamin D3 Receptor

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Synthetic 20‐Epi Analogs of Calcitriol are Potent Inducers of Target‐Gene Activation in Osteoblastic Cells

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