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1.
Chem Biodivers ; 20(9): e202300851, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37584103

ABSTRACT

In our search for peroxisome proliferator-activated receptor (PPAR) agonists, five undescribed compounds, namely two acyclic diterpenes (1 and 2; cladopsol A and cladopsol B), two sesquiterpenes (3 and 4; cladopsol C and cladopsol D), and one C21-ecdysteroid (5; cladopsol E), and 15 known compounds were isolated from the jellyfish-derived fungus - Cladosporium oxysporum. The structures of the undescribed compounds were defined using UV, NMR, HR-ESI-MS, and electronic circular dichroism (ECD) spectroscopy and a modified Mosher's method. Luciferase reporter assay and docking analysis suggested that cladopsol B may function as a PPAR-γ partial agonist with a potential antidiabetic lead which may evade the side effects of full agonists. Moreover, cladopsol B stimulated glucose uptake in HepG2 cells with an efficacy comparable to that of rosiglitazone, but with less side effect induced by lipid accumulation in 3T3-L1 cells. Therefore, cladopsol B could serve as a molecular skeleton in a study of advanced antidiabetic lead with less side effect.


Subject(s)
PPAR-gamma Agonists , Peroxisome Proliferator-Activated Receptors , Hypoglycemic Agents/pharmacology , Cladosporium , PPAR gamma/agonists
2.
Eur J Med Chem ; 180: 86-98, 2019 Oct 15.
Article in English | MEDLINE | ID: mdl-31301566

ABSTRACT

The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound 5m, which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound 5m suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE2, NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized 5m as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Drug Design , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cell Survival/drug effects , Cells, Cultured , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , RAW 264.7 Cells , Sheep , Structure-Activity Relationship , Urochordata
3.
Eur J Med Chem ; 157: 1192-1201, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30193217

ABSTRACT

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J2 (15 d-PGJ2). The exocyclic enone moiety of 15 d-PGJ2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.


Subject(s)
Drug Design , PPAR gamma/agonists , Prostaglandin D2/analogs & derivatives , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Ligands , Models, Molecular , Molecular Structure , Prostaglandin D2/chemical synthesis , Prostaglandin D2/chemistry , Prostaglandin D2/pharmacology , Rats , Structure-Activity Relationship
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