Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

Lin, Zongtao; Marepally, Srinivasa R.; Ma, Dejian; Myers, Linda K.; Postlethwaite, Arnold E.; Tuckey, Robert C.; Cheng, Chloe; Kim, Tae Kang; Yue, Junming; Slominski, Andrzej; Miller, Duane D.; Li, Wei

doi:10.1021/acs.jmedchem.5b00881

Cited by 23 publications

(46 citation statements)

References 30 publications

(98 reference statements)

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“…While originally produced by enzymatic synthesis in amounts enabling identification, chemical routes of synthesis for 20(OH)D3, 20,23(OH) 2 D3 and 20,24(OH) 2 D3 have now been established [64, 65, 67–69] which also confirmed that the enzymatically produced 20(OH)D3 is the 20 S enantiomer [67]…”

Section: New Pathways Of Vitamin D Activationmentioning

confidence: 99%

“…20(OH)D3 and its hydroxymetabolites exert prodifferentiation, antiproliferative, and antiinflammatory activities on skin cells, comparable or better than that of 1,25(OH) 2 D3 [53, 64, 65, 67, 70, 83–92]. 20(OH)D3 shows antifibrotic properties both in vitro [87–89] and in an in vivo mouse model of bleomycin induced scleroderma [89].…”

Section: Biological Activity Of Cyp11a1-derived Vitamin D Hydroxydmentioning

confidence: 99%

“…This was further substantiated by the ability of CYP11A1-derived D3 hydroxymetabolites to translocate VDR to the nucleus with high affinity [53, 61, 92]. However, they differ substantially from 1,25(OH) 2 D3 in that these metabolites lack calcemic activity (as described above), act as very poor activators of CYP24A1 expression [53, 84, 86, 95] and have very poor activity on a synthetic VDRE promoter construct that was however improved by hydroxylation in position C1α [64, 65]. …”

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

“…1α(OH) derivatives generally have better docking scores in agreement with their higher efficiency to translocate VDR to nucleus. Furthermore, interaction with VDRE [53, 64, 65, 84, 86, 95] or with specific coactivators (Fig. 2) is greatly enhanced or requires, respectively, the presence of the 1α(OH) group in the novel secosteroids.…”

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

“…It is interesting that antiproliferative and prodifferentiation or immunomodulatory effects of compounds with and without the 1α(OH) group, on human skin cells or immune cells, are either similar or show cell type and phenotypic trait-dependent differences (Fig. 1)[64, 65, 90, 92, 95]. Only a few secosteroids may potentially interact with the non-genomic site including 1α,25(OH) 2 D3, 23 S (OH)D3 (which can potentially be derived from CYP11A1 action on vitamin D3), and the products of 1,25(OH) 2 D3 catabolism, 24 R ,25(OH) 2 D3 and calcitroic acid..…”

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

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Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Slominski

Kim²,

Hobrath

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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126

143

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The classical pathway of vitamin D activation follows the sequence D3→25(OH)D3→1,25(OH)2D3 with the final product acting on the receptor for vitamin D (VDR). An alternative pathway can be started by the action of CYP11A1 on the side chain of D3, primarily producing 20(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3 and 17,20,23(OH)3D3. Some of these metabolites are hydroxylated by CYP27B1 at C1α, by CYP24A1 at C24 and C25, and by CYP27A1 at C25 and C26. The products of these pathways are biologically active. In the epidermis and/or serum or adrenals we detected 20(OH)D3, 22(OH)D3, 20,22(OH)2D3, 20,23(OH)2D3, 17,20,23(OH)3D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,22(OH)3D3, 20,24(OH)2D3, 1,20,24(OH)3D3, 20,25(OH)2D3, 1,20,25(OH)3D3, 20,26(OH)2D3 and 1,20,26(OH)3D3. 20(OH)D3 and 20,23(OH)2D3 are non-calcemic, while the addition of an OH at C1α confers some calcemic activity. Molecular modeling and functional assays show that the major products of the pathway can act as “biased” agonists for the VDR with high docking scores to the ligand binding domain (LBD), but lower than that of 1,25(OH)2D3. Importantly, cell based functional receptor studies and molecular modeling have identified the novel secosteroids as inverse agonists of both RORα and RORγ receptors. Specifically, they have high docking scores using crystal structures of RORα and RORγ LBDs. Furthermore, 20(OH)D3 and 20,23(OH)2D3 have been tested in cell model that expresses a Tet-on RORα or RORγ vector and a RORE-LUC reporter (ROR-responsive element), and in a mammalian 2-hybrid model that test interactions between an LBD-interacting LXXLL-peptide and the LBD of RORα/γ. These assays demonstrated that the novel secosteroids have ROR-antagonist activities that were further confirmed by the inhibition of IL17 promoter activity in cells overexpressing RORα/γ. In conclusion, endogenously produced novel D3 hydroxy-derivatives can act both as “biased” agonists of the VDR and/or inverse agonists of RORα/γ. We suggest that the identification of large number of endogenously produced alternative hydroxy-metabolites of D3 that are biologically active, and of possible alternative receptors, may offer an explanation for the pleiotropic and diverse activities of vitamin D, previously assigned solely to 1,25(OH)2D3 and VDR.

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Section: New Pathways Of Vitamin D Activationmentioning

confidence: 99%

Section: Biological Activity Of Cyp11a1-derived Vitamin D Hydroxydmentioning

confidence: 99%

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

Section: Receptors For Cyp11a1-derived D3 Hydroxymetabolitesmentioning

confidence: 99%

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Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Slominski

Kim²,

Hobrath

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

126

143

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Stereoselective Palladium‐Catalyzed Approach to Vitamin D₃ Derivatives in Protic Medium

Carballa

Sigüeiro

Rodríguez-Docampo

et al. 2018

Chemistry A European J

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We describe an efficient convergent synthesis of vitamin D metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D and 3-epi-vitamin D metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.

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The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers

Słomiński

Brożyna

Żmijewski

et al. 2020

Advances in Experimental Medicine and Biology

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Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical ( 1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and nongenomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.

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Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

Cited by 23 publications

References 30 publications

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Stereoselective Palladium‐Catalyzed Approach to Vitamin D₃ Derivatives in Protic Medium

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers

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Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

Cited by 23 publications

References 30 publications

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Stereoselective Palladium‐Catalyzed Approach to Vitamin D3 Derivatives in Protic Medium

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers

Contact Info

Product

Resources

About

Stereoselective Palladium‐Catalyzed Approach to Vitamin D₃ Derivatives in Protic Medium