Design and synthesis of BAP-1 inhibitors

Background: Tumors pose a severe threat to human health, with malignant tumors requiring complex targeted therapies. BRCA1-binding protein 1 (BAP1), a key deubiquitinase, plays dual roles in tumorigenesis and progression, making it a promising therapeutic target. The second-generation BAP1 inhibitor IBAP-II exhibits good activity but suffers from poor solubility, limiting its clinical application. Objectives: To design and synthesize novel BAP1 inhibitors with improved properties based on IBAP-II, addressing its solubility issue and enhancing inhibitory potential. Methods: Using IBAP-II as the lead compound, five novel compounds (6-nitroquinoline, 5-nitroindole and 7-nitroquinoline derivatives) were synthesized via Michael addition and Suzuki-Miyaura reactions. Structural confirmation was performed by ¹H NMR spectroscopy. Results: All five compounds were successfully synthesized with yields ranging from 27.86% to 51.07%. NMR data validated their target structures and structural modifications (e.g., hydroxyl/nitro relocation, ring structure adjustment) were confirmed to potentially improve solubility and binding affinity. Conclusion: This study provides feasible synthetic routes for novel BAP1 inhibitors with optimized structures, laying a foundation for subsequent biological activity evaluations and offering new prospects for targeted tumor therapy, especially for small cell lung cancer.