Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, India.
Department of Chemistry, Indian Institute of Technology Hyderabad, Sangareddy, India.
Chem Biol Drug Des. 2021 Jun;97(6):1170-1184. doi: 10.1111/cbdd.13839. Epub 2021 Apr 7.
DNA alkylation damage, emanating from the exposure to environmental alkylating agents or produced by certain endogenous metabolic processes, affects cell viability and genomic stability. Fe(II)/2-oxoglutarate-dependent dioxygenase enzymes, such as Escherichia coli AlkB, are involved in protecting DNA from alkylation damage. Inspired by the natural product indenone derivatives reported to inhibit this class of enzymes, and a set of 2-chloro-3-amino indenone derivatives was synthesized and screened for their inhibitory properties against AlkB. The synthesis of 2-chloro-3-amino indenone derivatives was achieved from 2,3-dichloro indenones through addition-elimination method using alkyl/aryl amines under catalyst-free conditions. Using an in vitro reconstituted DNA repair assay, we have identified a 2-chloro-3-amino indenone compound 3o to be an inhibitor of AlkB. We have determined the binding affinity, mode of interaction, and kinetic parameters of inhibition of 3o and tested its ability to sensitize cells to methyl methanesulfonate that mainly produce DNA alkylation damage. This study established the potential of indenone-derived compounds as inhibitors of Fe(II)/2-oxoglutarate-dependent dioxygenase AlkB.
DNA 烷化损伤源于环境烷化剂的暴露或某些内源性代谢过程产生，会影响细胞活力和基因组稳定性。Fe(II)/2-氧代戊二酸依赖性双加氧酶（如大肠杆菌 AlkB）参与保护 DNA 免受烷化损伤。受报道能抑制此类酶的天然产物茚酮衍生物的启发，我们合成了一组 2-氯-3-氨基茚酮衍生物，并对其抑制 AlkB 的特性进行了筛选。通过使用烷基/芳基胺在无催化剂条件下通过加成消除法，从 2,3-二氯茚酮合成了 2-氯-3-氨基茚酮衍生物。通过体外重建的 DNA 修复测定，我们发现 2-氯-3-氨基茚酮化合物 3o 是 AlkB 的抑制剂。我们已经确定了 3o 的结合亲和力、相互作用模式和抑制动力学参数，并测试了它使细胞对主要产生 DNA 烷化损伤的甲基甲磺酸磺酸盐敏感的能力。这项研究确立了茚酮衍生化合物作为 Fe(II)/2-氧代戊二酸依赖性双加氧酶 AlkB 抑制剂的潜力。
