Synthesis of novel benzylidene analogues of betulinic acid as potent cytotoxic agents

• Published in: European journal of medicinal chemistry 2017-07, Vol.135, p.517-530
• Main Authors: Gupta, Nidhi, Rath, Santosh K., Singh, Jasvinder, Qayum, Arem, Singh, Shashank, Sangwan, Payare L.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Benzylidene Compounds - pharmacology; Benzylidene derivatives; Betulinic acid; Cell Line, Tumor; Cell Proliferation - drug effects; Colony formation; Cytotoxicity; Cytotoxins - chemical synthesis; Cytotoxins - chemistry; Cytotoxins - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.04.062

Different benzylidene derivatives (15a-o and 16a-o) of betulinic acid were designed and synthesized in an effort to develop potent anticancer agents. All the synthesized derivatives along with betulinic acid were evaluated for cytotoxicity against a panel of five different human cancer cell lines A-549 (Lung), PC-3 (Prostate), HCT 116 (Colon), MCF-7 (Breast) and MIA PaCa-2 (Pancreatic) using SRB assay. Pharmacological results showed that compounds 15b, 15c, 15i, 15k, 16a-c and 16l were found to have promising cytotoxic profile against various cancer cell lines tested (IC50 1–2 μM). Best results were observed for compound 16c with IC50 values 1.5, 1.6, 1.36, 3.5 and 3.2 μM against A-549, PC-3, HCT 116, MCF-7 and MIA PaCa-2 cell lines, respectively. Mechanistic study of compound 16c revealed that it inhibits the colony formation and restrict the migration in HCT 116 cells in vitro. It also induces growth arrest with characterized morphological changes and loss of mitochondrial membrane potential (MMP) in a concentration dependent manner. Design and synthesis of C-2 and C-3 derived benzylidene analogues of betulinic acid as potent cytotoxic agents. [Display omitted] •Synthesis of 31 betulinic acid derivatives.•Several derivatives were active against human cancer cell lines.•The molecules inhibits the colony formation and restrict the migration of HCT-116 cells.