Lithocholic acid-based design of noncalcemic vitamin D receptor agonists

Gaikwad, Sunil; González, Carmen; Vilariño, Daniel; Lasanta, Gonzalo; Villaverde, M. C.; Mouriño, Antonio; Verlinden, Lieve; Verstuyf, Annemieke; Peluso‐Iltis, Carole; Rochel, Natacha; Berkowska, Klaudia; Marcinkowska, Ewa

doi:10.1016/j.bioorg.2021.104878

Cited by 6 publications

(4 citation statements)

References 47 publications

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“…The hydroxyl group in the 3-substituent also forms direct hydrogen bonds with two histidine residues, His301 and His393. Recently, compound 3 ( Dcha-20 ) was reported to have lower calcemic activity than 1α,25(OH) 2 D 3 ( 1 ) [ 11 ], which would be favorable for clinical application, but preliminary studies on the pharmacokinetics of 3 ( Dcha-20 ) indicated that it is eliminated very quickly in mice. The carboxyl group of 3 ( Dcha-20 ) appears to be important for both the potent vitamin D activity and the pharmacokinetic properties.…”

Section: Discussionmentioning

confidence: 99%

“…In HL-60 cell differentiation-inducing assay, 3 was more potent than 1 . Gaikwad, S. et al recently reported that 3 shows potent vitamin D activity with a lower calcemic activity than 1 [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of the crystal structure of VDR ligand-binding domain (LBD) bound to 3 ( Dcha-20 ) showed that the 3-substituent forms direct hydrogen bonds with the two histidine residues His301 and His393, like the 25-hydroxyl group of 1α,25(OH) 2 D 3 ( 1 ), but different from the indirect interaction, via a water molecule, of the 3-hydroxyl group of LCA ( 2 ) with the same amino acid residues of the VDR [ 8 , 11 ]. The carboxyl group of 3 forms hydrogen bonds with Tyr143 and Ser274, as in the case of 1α,25(OH) 2 D 3 ( 1 ) or LCA ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

et al. 2022

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1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

et al. 2022

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“…It is noteworthy that not only analogs of 1,25D can be used as agonists of VDR: lithocholic acid (LCA) is a natural ligand, and a very weak agonist of VDR. Modifications of LCA structure can substantially increase the pro-differentiation potency of LCA, without affecting calcium phosphate homeostasis [ 63 , 64 , 65 ]. Unfortunately, the clinical trials using analogs of 1,25D were also far from these for ATRA in APL [ 66 ].…”

Section: Low-calcemic Analogs Of 125dmentioning

confidence: 99%

Vitamin D Derivatives in Acute Myeloid Leukemia: The Matter of Selecting the Right Targets

Marcinkowska

2022

Nutrients

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Acute myeloid leukemia (AML) is an aggressive and often fatal hematopoietic malignancy. A very attractive way to treat myeloid leukemia, called “differentiation therapy”, was proposed when in vitro studies showed that some compounds are capable of inducing differentiation of AML cell lines. One of the differentiation-inducing agents, all-trans-retinoic acid (ATRA), which can induce granulocytic differentiation in AML cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a chromosomal translocation. ATRA has greatly improved the treatment of APL. Since 1,25-dihydroxyvitamin D (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs was widely accepted. However, early clinical trials in which cancer patients were treated either with 1,25D or with analogs did not lead to conclusive results. Recent results have shown that AML types with certain mutations, such as isocitrate dehydrogenase (IDH) mutations, may be the right targets for differentiation therapy using 1,25D, due to upregulation of vitamin D receptor (VDR) pathway.

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