Abd Al Moaty Mohamed N, El Kilany Yeldez, Awad Laila Fathy, Ibrahim Nihal Ahmed, Abu-Serie Marwa M, El-Yazbi Amira, Teleb Mohamed
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
Arch Pharm (Weinheim). 2024 Jan;357(1):e2300454. doi: 10.1002/ardp.202300454. Epub 2023 Oct 22.
Breast cancer continues to be the most frequent cancer worldwide. In practice, successful clinical outcomes were achieved via targeting DNA. Along with the advances in introducing new DNA-targeting agents, the "sugar approach" design was employed herein to develop new intercalators bearing pharmacophoric motifs tethered to carbohydrate appendages. Accordingly, new benzimidazole acyclic C-nucleosides were rationally designed, synthesized and assayed via MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay to evaluate their cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells compared to normal fibroblasts (Wi-38), compared to doxorubicin. (1S,2R,3S,4R)-2-(1,2,3,4,5-Pentahydroxy)pentyl-1H-5,6-dichlorobenzimidazole 7 and (1S,2R,3S,4R)-2-(1,2,3,4,5-pentahydroxy)pentyl-1H-naphthimidazole 13 were the most potent and selective derivatives against MCF-7 (half-maximal inhibitory concentration [IC ] = 0.060 and 0.080 µM, selectivity index [SI] = 9.68 and 8.27, respectively) and MDA-MB-231 cells (IC = 0.299 and 0.166 µM, SI = 1.94 and 3.98, respectively). Thus, they were identified as the study hits for mechanistic studies. Both derivatives induced DNA damage at 0.24 and 0.29 μM, respectively. The DNA damage kinetics were studied compared to doxorubicin, where they both induced faster damage than doxorubicin. This indicated that 7 and 13 showed a more potent DNA-damaging effect than doxorubicin. Docking simulations within the DNA double strands highlighted the role of both the heterocyclic core and the sugar side chain in exhibiting key H-bond interactions with DNA bases.
乳腺癌仍然是全球最常见的癌症。在实践中，通过靶向DNA取得了成功的临床结果。随着新型DNA靶向药物的不断发展，本文采用“糖类方法”设计，开发了带有与碳水化合物附属物相连的药效基团的新型嵌入剂。因此，合理设计、合成了新型苯并咪唑无环C-核苷，并通过MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑）试验进行检测，以评估它们与阿霉素相比，对MCF-7和MDA-MB-231乳腺癌细胞以及正常成纤维细胞（Wi-38）的细胞毒性。（1S,2R,3S,4R）-2-（1,2,3,4,5-五羟基）戊基-1H-5,6-二氯苯并咪唑7和（1S,2R,3S,4R）-2-（1,2,3,4,5-五羟基）戊基-1H-萘并咪唑13是针对MCF-7（半数最大抑制浓度[IC₅₀]分别为0.060和0.080 μM，选择性指数[SI]分别为9.68和8.27）和MDA-MB-231细胞（IC₅₀分别为0.299和0.166 μM，SI分别为1.94和3.98）最有效和最具选择性的衍生物。因此；它们被确定为进行机制研究的研究靶点。两种衍生物分别在0.24和0.29 μM时诱导DNA损伤。与阿霉素相比，研究了DNA损伤动力学，结果表明它们两者诱导的损伤都比阿霉素更快。这表明7和13显示出比阿霉素更强的DNA损伤作用。DNA双链内的对接模拟突出了杂环核心和糖侧链在与DNA碱基表现出关键氢键相互作用中的作用。
