Isatin Derived Spirocyclic Analogues with α‑Methylene-γ-butyrolactone as Anticancer Agents: A Structure–Activity Relationship Study

• Published in: Journal of medicinal chemistry Vol. 59; no. 10; pp. 5121 - 5127
• Main Authors: Rana, Sandeep, Blowers, Elizabeth C, Tebbe, Calvin, Contreras, Jacob I, Radhakrishnan, Prakash, Kizhake, Smitha, Zhou, Tian, Rajule, Rajkumar N, Arnst, Jamie L, Munkarah, Adnan R, Rattan, Ramandeep, Natarajan, Amarnath
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-05-2016
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isatin - chemistry; Isatin - pharmacology; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00400

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.