Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity

DeLuca, Hector F.; Plum, Lori A.

doi:10.1016/b978-0-12-381978-9.10074-5

Cited by 2 publications

(1 citation statement)

References 55 publications

(61 reference statements)

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“…There are some promising analogs that retain high pro-differentiating and anti-proliferative activities in vitro and express low calcemic activities in vivo. Even though many interesting analogs have been made, a clear pattern of structure-function relationship did not emerge (21). How complicated such structure-function relationships could be is well illustrated by a series of vitamin D 2 analogs with extended and branched side-chains (22).…”

Section: Discussionmentioning

confidence: 99%

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

et al. 2012

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1,25-Dihydroxyvitamin D3 (1,25D) is implicated in many cellular functions including cell proliferation and differentiation, thus, exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D are its potent calcemic and phosphatemic activities. Therefore, synthetic analogs of 1,25D for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. Previously, we described pro-differentiating effects of vitamin D2 analogs with extended and branched side-chains. Analogs with side-chains extended by a pair of one (PRI-1906) or two carbon units (PRI-1907) displayed elevated cell-differentiating activity towards some acute leukemia cell lines (AML) in comparison to 1,25D. In this study, the potential mechanism of this superagonistic activity of the analogs was addressed. At first, possible differences in the expression of CYP24A1, a major catabolizing enzyme for vitamin D compounds and resulting differences in the degradation of analogs were investigated. In addition, interactions of the analogs with vitamin D receptor (VDR) and resulting activation of CCAAT-enhancer-binding protein β (C/EBPβ) were studied. The results obtained show that superagonistic pro-differentiating activities of analogs PRI-1906 and PRI-1907 do not seem to be caused by their altered catabolism, but most probably by altered interactions with VDR and resulting downstream proteins.

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Section: Discussionmentioning

confidence: 99%

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

et al. 2012

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Retiferols – synthesis and biological activity of a conceptually novel class of vitamin D analogs

Bolla¹,

Marcinkowska²,

Brown³

et al. 2014

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Docking experiments and molecular modeling have shown that positioning of vitamin D analog at the LBD of VDR is not disturbed by deletion of a large portion of the vitamin D, exactly as hypothesized. Twenty years of structural modifications have shown that removal of the CD-ring fragment and regioselective methylation results in an almost complete loss of the undesired calcemic activity of retiferol while gaining the agonistic activity comparable to that of 1,25-(OH)2D3.

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Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity

Cited by 2 publications

References 55 publications

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

Retiferols – synthesis and biological activity of a conceptually novel class of vitamin D analogs

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