Molecular editing of NSC-666719enabling discovery of benzodithiazinedioxide-guanidines as anticancer agentsElectronic supplementary information (ESI) available. CCDC 2269969. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3md00648d

DNA polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both in vitroreconstituted and in vivointact cell systems. Compound 10edemonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.