| Autor: |
Atigadda VR, Kashyap MP, Yang Z, Chattopadhyay D, Melo N, Sinha R, Belyaeva OV, Chou CF, Chang PL, Kedishvili NY, Grubbs CJ, Renfrow MB, Muccio DD, Elmets CA, Athar M |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2022 Nov 10; Vol. 65 (21), pp. 14409-14423. Date of Electronic Publication: 2022 Nov 01. |
| DOI: |
10.1021/acs.jmedchem.2c00735 |
| Abstrakt: |
Compound 1 is a potent rexinoid that is highly effective in cancer chemoprevention but elevates serum triglycerides. In an effort to separate the lipid toxicity from the anticancer activity of 1 , we synthesized four new analogs of rexinoid 1 , of which three rexinoids did not elevate serum triglycerides. Rexinoids 3 and 4 are twice as potent as rexinoid 1 in binding to Retinoid X receptor (RXR). All-trans retinoic acid (ATRA) plays a key role in maintaining skin homeostasis, and rexinoids 3-6 are highly effective in upregulating the genes responsible for the biosynthesis of ATRA. Inflammation plays a key role in skin cancer, and rexinoids 3 and 4 are highly effective in diminishing LPS-induced inflammation. Rexinoids 3 and 4 are highly effective in preventing UVB-induced nonmelanoma skin cancer (NMSC) without displaying any overt toxicities. Biophysical studies of rexinoids 3 and 5 bound to hRXRα-ligand binding domain (LBD) reveal important conformational and dynamical differences in the ligand binding domain. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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