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In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the CHNHSOR-m moiety at C-3 position of the isocoumarin ring was favorable when the R was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.
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http://dx.doi.org/10.1016/j.bioorg.2022.105667 | DOI Listing |
J Antibiot (Tokyo)
November 2023
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantan xili No.1, Beijing, 100050, China.
Three isocoumarins, including two new compounds, (±) pestalactone D (1) and pestapyrone F (2), as well as one known compound, pestapyrone D (3), were isolated from the culture of the endolichenic Pestalotiopsis rhododendri LF-19-12. The planar structures of all compounds were elucidated by NMR and MS spectra. And the absolute configurations of 1 were confirmed by single crystal X-ray diffraction analysis, indicative of it as a racemate of 4S/12S and 4R/12R enantiomers.
View Article and Find Full Text PDFChemistry
August 2023
Institute of Chemistry, Saint Petersburg State University (SPbU), Sankt-Peterburg, 199034 Saint Petersburg, Russia.
Fluorescent isocoumarin-fused cycloalkynes, which are reactive in SPAAC and give fluorescent triazoles regardless of the azide nature, have been developed. The key structural feature that converts the non-fluorescent cycloalkyne/triazole pair to its fluorescent counterpart is the pi-acceptor group (COOMe, CN) at the C6 position of the isocoumarin ring. The design of the fluorescent cycloalkyne/triazole pairs is based on the theoretical study of the S1 state deactivation mechanism of the non-fluorescent isocoumarin-fused cycloalkyne IC9O using multi-configurational ab initio and DFT methodologies.
View Article and Find Full Text PDFCommun Chem
November 2022
School of Chemistry, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi'an Key Laboratory of Sustainable Energy Materials Chemistry, Xi'an Jiaotong University (XJTU), 710049, Xi'an, P. R. China.
Diaryliodonium salts have been extensively applied in organic synthesis as aryl cation equivalents. However, in the electrophilic reactions with alkenes or alkynes, only the electrophilic carbon of the diaryliodonium salts was involved while the other part of the aryl ring was not utilized. Herein, a reaction pattern of diaryliodonium was reported as oxa-1,4-dipoles to undergo (4 + 2) cycloaddition reactions with alkynes.
View Article and Find Full Text PDFACS Omega
December 2022
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
A phytochemical investigation of the -hexane-soluble chemical constituents roots allowed for selection using a proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression monitoring assay in HepG2 cells. This led to the isolation of two previously undescribed isocoumarins of natural origin, 8'Z,11'Z-octadecadienyl-6,8-dihydroxyisocoumarin () and 3-pentadecyl-6,8-dihydroxyisocoumarin (), along with 20 previously reported compounds (-). All of the structures were established using NMR spectroscopic data and MS analysis.
View Article and Find Full Text PDFJ Agric Food Chem
November 2022
State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047, P.R. China.
Ochratoxin A (OTA) is an important mycotoxin detected in edible oil, and it can be effectively removed by classical edible oil refining processes. However, the fate of OTA in the refining process has not been reported. In this study, we systematically tracked the OTA changes during the oil refining process by fortifying 100 μg/kg OTA in crude rapeseed oil.
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