Novel triazole hybrids of myrrhanone C, a natural polypodane triterpene: Synthesis, cytotoxic activity and cell based studies

• Published in: European journal of medicinal chemistry Vol. 114; pp. 293 - 307
• Main Authors: Chandrashekhar, Madasu, Nayak, Vadithe Lakshma, Ramakrishna, Sistla, Mallavadhani, Uppuluri Venkata
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 23-05-2016
• Subjects: Anticancer activity; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Cell Cycle - drug effects; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hybrids; Membrane Potential, Mitochondrial - drug effects; Molecular Structure; Myrrhanone C; Structure-Activity Relationship; Triazoles; Triazoles - chemistry; Triazoles - pharmacology; Triterpene; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Myrrhanone C; Hybrids; Triazoles; Triterpene; Anticancer activity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.03.013

The 3-keto functionality in ring A of myrrhanone C, a natural bicyclic triterpene has been chemically modified and synthesized 27 novel triazole hybrids belonging to two different series in very good to excellent yields (66–83%). The synthesized compounds were thoroughly characterized by their spectroscopic data (IR, 1H&13C NMR, HRMS). All the synthesized compounds were evaluated for their cytotoxic potential against a panel of five human cancer cell lines by employing MTT assay using doxorubicin as the standard. In general the synthesized compounds showed anticancer activity against almost all the cell lines screened. Interestingly, the oxime based triazoles (4a–4n) showed higher activity than the benzylidene triazoles (6a–6m). Most significantly compound 4a showed potent activity against all the tested cell lines, especially against lung cancer (A-549) with an IC 50 of 6.16 μm. In view of their significant activity against lung cancer cell lines, compounds 4a and 4l were subjected to detailed biological studies, which revealed that they arrested cell cycle in G2/M phase and induced cell death by apoptosis that was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin V-FITC assay. These compounds will serve as lead molecules in the development of potent anticancer drug candidates especially for lung cancer.
Twenty seven novel triazole hybrids of myrrhanone C were synthesised and subjected to cell based studies and evaluated their anticancer potential against five human cancer cell lines. [Display omitted]
•The 3-keto functionality of myrrhanone C has been chemically modified and synthesized 27 novel triazole hybrids.•The synthesised compounds were evaluated against five human cancer cell lines.•The oxime based triazoles showed higher activity than the benzylidene triazoles.•Compound 4a showed highly potent activity against A-549 cell line.•Cell based studies were carried out on the potent compounds 4a and 4l.