背景:在各种癌症中通常观察到组蛋白脱乙酰酶(HDAC)和核糖核苷酸还原酶(RR)酶的异常表达。研究人员正在癌症研究中关注这些酶,目的是开发有效的化疗药物来治疗癌症。与单一疗法相比,用双重HDAC/RR抑制剂同时靶向HDAC和RR在癌症治疗中显示出增强的有效性。使其成为一个有前途的战略。
目的:本研究的目的是合成和评估1,10-菲咯啉基羟肟酸盐衍生物的抗癌特性,将其表征为一种新型的双重HDAC/RR抑制剂。
方法:N1-羟基-N8-(1,10-菲罗啉-5-基)辛二酰胺(PA),一种1,10-菲咯啉基羟肟酸盐衍生物,合成和结构表征。对该化合物进行了抗癌的体外评估,HDAC,和RR抑制活性。进一步研究了计算机对接和分子动力学模拟,以探索其与HDAC和RRM2的相互作用。
结果:结构证实的PA在SiHa细胞中表现出抗增殖活性,IC50为16.43μM。它对HDAC和RR显示出有效的抑制活性,IC50值为10.80μM和9.34μM,分别。HDAC和RR的共同抑制导致SiHa细胞凋亡诱导的细胞死亡,由活性氧(ROS)的积累介导。计算机对接研究表明,PA可以有效地结合HDAC同工型和RRM2的活性位点。此外,PA表现出与HDAC7更有利的相互作用,显示-9.633kcal/mol的对接评分,与标准HDAC抑制剂辛二酰苯胺异羟肟酸(SAHA)相比,对HDAC7的对接评分为-8.244kcal/mol。
结论:本研究强调了设计潜在的1,10-菲咯啉异羟肟酸衍生物作为新型的双重HDAC和RR抑制抗癌分子的前景。
BACKGROUND: Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy.
OBJECTIVE: The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor.
METHODS: The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2.
RESULTS: The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7.
CONCLUSIONS: The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.