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

• Published in: International journal of molecular sciences 2020-05, Vol.21 (10), p.3511
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 18βH-glycyrrhetinic acid; Acids; Acylation; Animal models; anti-inflammatory activity; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biocompatibility; Carboxyl group; Carrageenan; Caspases - metabolism; Cell Death - drug effects; Cell Proliferation - drug effects; Cervical cancer; Cervical carcinoma; Cervix; Cytotoxicity; derivatives; Elastase; Gelatinase B; Glycyrrhetinic Acid - chemical synthesis; Glycyrrhetinic Acid - chemistry; Glycyrrhetinic Acid - pharmacology; HeLa Cells; heterocyclic moiety; Humans; Hydroxyl groups; In vivo methods and tests; Inflammation; Inflammation - pathology; Inflammatory response; Intermediates; Macrophages; Melanoma; Melanoma, Experimental - pathology; Metabolites; Metastases; Mitochondria - drug effects; Mitochondria - metabolism; Neoplasm Metastasis; oxadiazole; Oxadiazoles; Oxadiazoles - chemistry; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Selectivity; Thrombin; Triterpenoids; Tumor cell lines; Tumor cells; γ-Interferon
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21103511

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- -acylated amidoxime -display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1',2',4'-oxadiazole analogs (median IC = 7.0 and 49.7 µM, respectively). 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 , showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 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. Additionally, the comprehensive in silico study revealed intermediate , bearing the -butyl moiety in -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 molecules with pronounced antitumor ( ) and anti-inflammatory ( ) activities.