Markov, Andrey V.; Sen’kova, Aleksandra V.; Popadyuk, Irina I.; Salomatina, Oksana V.; Logashenko, Evgeniya B.; Komarova, Nina I.; Ilyina, Anna A.; Salakhutdinov, Nariman F.; Zenkova, Marina A. published the artcile< Novel 3'-substituted-1',2',4'-oxadiazole derivatives of 18βH-glycyrrhetinic acid and their O-acylated amidoximes: synthesis and evaluation of antitumor and anti-inflammatory potential in vitro and in vivo>, Recommanded Product: N-Hydroxypropionimidamide, the main research area is oxadiazolyl oleanen preparation antitumor anti inflammatory agent SAR; acetoxy oxooleanen amidoxime preparation antitumor anti inflammatory agent SAR; 18βH-glycyrrhetinic acid; anti-inflammatory activity; antitumor activity; apoptosis; derivatives; heterocyclic moiety; metastasis; molecular docking; oxadiazole; target prediction.
A series of novel 18βH-glycyrrhetinic acid (GA) derivatives containing 3′-(alkyl/phenyl/pyridin(-2”, -3”, and -4”)-yl)-1′,2′,4′-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid’s carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates-O-acylated amidoxime I [R = Me, Et, i-Pr, t-Bu, etc]display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1′,2′,4′-oxadiazole analogs II [R = 2-pyridine, 3-pyridine, 4-pyridine] (median IC50 = 7.0 and 49.7μM, resp.). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2”, 3”, and -4”)-yl-1′,2′,4′-oxadiazole-bearing GA derivatives produced compounds III [R = 2-pyridine, 3-pyridine, 4-pyridine], showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed anal. of the antitumor activity of hit derivative III [R = 2-pyridine] revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Addnl., the comprehensive in silico study revealed intermediate I [R = t-Bu], bearing the tert-Bu moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFNγ in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure-activity relationship of 1′,2′,4′-oxadiazole-containing triterpenoids and reveal two hit mols. with pronounced antitumor III [R = 2-pyridine] and anti-inflammatory I [R = t-Bu] activities.
International Journal of Molecular Sciences published new progress about Amidoximes Role: PAC (Pharmacological Activity), RCT (Reactant), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), RACT (Reactant or Reagent), PREP (Preparation), USES (Uses). 29335-36-2 belongs to class alcohols-buliding-blocks, and the molecular formula is C3H8N2O, Recommanded Product: N-Hydroxypropionimidamide.
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