Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms

• Published in: Bioorganic chemistry Vol. 119; p. 105535
• Main Authors: Smirnova, Irina, Drăghici, George, Kazakova, Oxana, Vlaia, Lavinia, Avram, Stefana, Mioc, Alexandra, Mioc, Marius, Macaşoi, Ioana, Dehelean, Cristina, Voicu, Adrian, Şoica, Codruța
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.02.2022; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis - drug effects; Arylidene; Biochemistry & Molecular Biology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CAM assay; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chemistry, Organic; Claisen-Schmidt aldol condensation; Cytotoxicity; Dammarane triterpenoids; Dipterocarpol; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hollongdione; Humans; Life Sciences & Biomedicine; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Structure; NCI-60; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Physical Sciences; rtPCR; Science & Technology; Structure-Activity Relationship; Hollongdione; Dammarane triterpenoids; rtPCR; Claisen-Schmidt aldol condensation; Antiproliferative activity; CAM assay; Dipterocarpol; Arylidene; Cytotoxicity; NCI-60; CELLS; TRITERPENOIDS; ANGIOGENESIS; PGC1-ALPHA; TUMORS; BCL-2; BETULINIC ACID; METABOLISM; ANTICANCER DRUG SCREEN; EXPRESSION
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105535

[Display omitted] •Hollongdione arylidene derivatives were obtained by the Claisen-Schmidt condensation.•2,21-bis-[3-N-pyridinyl]-methylidenohollongdione 9 had the strongest antiproliferative effect.•This lead derivative revealed ex vivo antiangiogenic effect.•Compound 9 induced mitochondrial dysfunction by inhibition of mitochondrial respiration.•The lead compound 9 induced the overexpression of pro-apoptotic proteins Bax, Bak, Bad and Apaf1. The use of natural compounds as starting point for semisynthetic derivatives has already been proven as a valuable source of active anticancer agents. Hollongdione (4,4,8,14-tetramethyl-18-norpregnan-3,20-dion), obtained by few steps from dammarane type triterpenoid dipterocarpol, was chemically modified at C2 and C21 carbon atoms by the Claisen-Schmidt aldol condensation to give a series of arylidene derivatives. The anticancer activity of the obtained compounds was assessed on NCI-60 cancer cell panel, revealing strong antiproliferative effects against a large variety of cancer cells. 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 emerged as the most active derivative as indicated by its GI50 values in the micromolar range which, combined with its high selectivity index values, indicated its suitability for deeper biological investigation. The mechanisms involved in compound 9 antiproliferative activity, were investigated through in vitro (DAPI staining) and ex vivo (CAM assay) tests, which exhibited its apoptotic and antiangiogenic activities. In addition, compound 9 showed an overall inhibition of mitochondrial respiration. rtPCR analysis identified the more intimate activity at pro-survival/pro-apoptotic gene level. Collectively, the hollongdione derivative stand as a promising therapeutic option against melanoma and breast cancer provided that future in vivo analysis will certify its clinical efficacy.