Krishna Rao Vajja, Paul Subarno, Gulkis Mitchell, Shen Zhihang, Nair Haritha, Singh Amandeep, Li Chenglong, Sharma Arun K, Çağlayan Melike, Das Chinmay, Das Biswajit, Kundu Chanakya N, Narayan Satya, Guchhait Sankar K
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Sector 67, SAS Nagar Mohali Punjab 160062 India
Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University Campus-11, Patia Bhubaneswar-751024 Odisha India
RSC Med Chem. 2024 Jan 30;15(3):937-962. doi: 10.1039/d3md00648d. eCollection 2024 Mar 20.
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 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 and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both reconstituted and 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.
DNA聚合酶β（Polβ）对于DNA损伤修复的碱基切除修复（BER）途径至关重要，是抑制肿瘤发生以及癌症化疗干预的一个有吸引力的靶点。在本研究中，研究了一种基于生物活性药物骨架跳跃的分子编辑独特策略，该策略导致了具有Polβ抑制活性的新分子基序的开发。制备了NSC化合物及其类似物（两个系列），重点关注基于药效团的分子多样性。大多数化合物显示出比母体更高的活性，并表现出对细胞凋亡的影响。在重组和完整细胞系统中评估了Polβ的抑制活性。化合物10e表现出显著的Polβ相互作用和抑制特性，包括直接、非共价、可逆和相当的结合亲和力。所研究的方法是有用的，并且发现的新型类似物具有作为抗癌治疗药物开发的高潜力。
