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Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents
Vajja Krishna Rao1, Subarno Paul2, Mitchell Gulkis3
1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Sector 67, SAS Nagar Mohali Punjab 160062 India skguchhait@niper.ac.in.
Abstract:
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-666719 was 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-666719 and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated 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.
Insights
Researchers developed novel DNA polymerase β (Polβ) inhibitors by modifying NSC-666719. These new compounds show enhanced Polβ inhibition and potential as anticancer therapeutics, impacting DNA repair and cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- DNA polymerase β (Polβ) is vital for base excision repair (BER) in DNA damage repair.
- Polβ is a key target for cancer therapy and suppressing tumorigenesis.
Purpose of the Study:
- To develop novel Polβ inhibitors using scaffold-hopping molecular editing of NSC-666719.
- To explore pharmacophore-based molecular diversity for enhanced Polβ inhibitory activity.
Main Methods:
- Synthesis of NSC compound analogs (two series) based on scaffold-hopping.
- Evaluation of Polβ inhibitory activity in vitro and in vivo systems.
- Assessment of apoptosis-inducing effects of the synthesized compounds.
Main Results:
- Most analogs exhibited higher Polβ inhibitory activity than the parent compound NSC-666719.
- Compound 10e showed significant direct, non-covalent, reversible Polβ inhibition with comparable binding affinity.
- Synthesized compounds demonstrated effects on apoptosis.
Conclusions:
- The scaffold-hopping approach successfully generated novel Polβ inhibitors.
- The discovered analogs hold significant potential for development as anticancer therapeutics.
- These findings offer new strategies for cancer treatment targeting DNA repair mechanisms.
