AUTHOR=Amin Hawraz Ibrahim M. , Ruiz-Pino Francisco , Collado Juan A. , Appendino Giovanni , Tena-Sempere Manuel , Munoz Eduardo , Caprioglio Diego 

TITLE=Synthesis and biological evaluation of hydroxamate isosteres of acidic cannabinoids

JOURNAL=Frontiers in Natural Products

VOLUME=2

YEAR=2023

URL=https://www.frontiersin.org/journals/natural-products/articles/10.3389/fntpr.2023.1190053

DOI=10.3389/fntpr.2023.1190053

ISSN=2813-2602

ABSTRACT=<p>Despite their early discovery, the bioactivity of acidic cannabinoids was long overlooked. Issues of stability and a pharmacological focus on Δ<sup>9</sup>-THC and its biological profile combined to relegate the non-narcotic native form of phytocannabinoids to a sort of investigational limbo. Recent studies have disclosed an attractive bioactivity profile for specific acidic phytocannabinoids but concerns about their limited stability have remained substantially unaddressed. To solve this issue, we have developed the hydroxamate derivatives of Δ<sup>8</sup>-tetrahydrocannabinolic acid-A (Δ<sup>8</sup>-THCA-AH, <bold>6</bold>) and cannabidiolic acid (CBDAH, <bold>5</bold>) as novel acidic cannabinoid bioisosteres, and we report here their synthesis and bioactivity profile against specific cannabinoid targets, as well as promising <italic>in vivo</italic> activity in a murine model of polycystic ovary syndrome (PCOS) associated with obesity.</p>