Dangroo Nisar A, Moussa Ziad, Alluhaibi Mustafa S, Alsimaree Abdulrahman A, Hawsawi Mohammed B, Alsantali Reem I, Singh Jasvinder, Gupta Nidhi, S M Basavarajaiah, Karunakar Prashantha, Mir J M, Rather Manzoor A, Ahmed Saleh A
Department of Chemistry, Islamic University of Science and Technology Awantipora J & K 192122 India
Department of Chemistry, College of Science, United Arab Emirates University P. O. Box 15551 Al Ain United Arab Emirates.
RSC Adv. 2025 May 8;15(19):15164-15177. doi: 10.1039/d5ra01038a. eCollection 2025 May 6.
In this report, novel derivatives of betulinic acid were designed and synthesized by targeting the C-3-OH group and C-20 olefinic bond in an endeavour to develop potent antitumor agents. These analogs were screened for their anticancer activity against six different human cancer cell lines including breast cancer MCF-7, lung cancer A549, colon cancer HCT-116, leukemia MOLT-4, prostate carcinoma cell PC-3 and pancreatic cancer cell Miapaca-2 by MTT assay. Many derivatives displayed better cytotoxicity than the parent compound BA. More significantly compounds 9b, 9e, 10 and 11a were found to have more promising activity than BA. Compound 11a was the most potent analog with IC values of 7.15 (MCF-7), 8.0 (A549), 3.13 (HCT-116), 13.88 (MOLT-4), 8.0 (PC-3) and 6.96 (MiaPaCa-2) μM. In addition to experimental investigations, aspects were evaluated for the parent compound, BA and 11a derivative based on its potential bioactive behaviour. The representative compounds were optimized structurally using density functional theory (DFT). GaussView 6.1 graphical interface associated GAUSSIAN 09 (Revision C.01) software package was used for the calculations under 6-311g(d,p)/B3LYP formalism using under a SMD model (water as solvent) for the parent compound BA and 11a to explain the respective bioactive behaviour. This was followed by molecular docking studies suggesting that compound 11a binds efficiently with all the three proteins with the docking score of -7.2 kcal mol in the case of matrix metalloproteinase-2 (PDB ID: 1HOV) and poly[ADP-ribose] polymerase-1 (PDB ID: 1UK0) and -6.7 kcal mol in the case of TRAF2 (PDB ID: 2X7F). Further, molecular dynamics studies between 11a and the three proteins were carried out using Desmond Maestro v11.3 to study protein-ligand interactions and protein stability.
在本报告中，通过靶向桦木酸的C-3-OH基团和C-20烯烃键设计并合成了新型桦木酸衍生物，以期开发出有效的抗肿瘤药物。通过MTT法对这些类似物针对六种不同的人类癌细胞系进行抗癌活性筛选，这些细胞系包括乳腺癌MCF-7、肺癌A549、结肠癌HCT-116、白血病MOLT-4、前列腺癌细胞PC-3和胰腺癌细胞Miapaca-2。许多衍生物表现出比母体化合物BA更好的细胞毒性。更显著的是，发现化合物9b、9e、10和11a具有比BA更有前景的活性。化合物11a是最有效的类似物，其IC值分别为7.15（MCF-7）、8.0（A549）、3.13（HCT-116）、13.88（MOLT-4）、8.0（PC-3）和6.96（MiaPaCa-2）μM。除了实验研究外，还基于母体化合物BA和11a衍生物的潜在生物活性行为对其进行了评估。使用密度泛函理论（DFT）对代表性化合物进行结构优化。使用与GAUSSIAN 09（修订版C.01）软件包相关联的GaussView 6.1图形界面，在6-311g(d,p)/B3LYP形式体系下，以SMD模型（水作为溶剂）对母体化合物BA和11a进行计算，以解释各自的生物活性行为。随后进行分子对接研究，结果表明化合物11a与所有三种蛋白质都能有效结合，在基质金属蛋白酶-2（PDB ID：1HOV）和聚[ADP-核糖]聚合酶-1（PDB ID：1UK0）的情况下对接分数为-7.2 kcal mol，在TRAF2（PDB ID：2X7F）的情况下对接分数为-6.7 kcal mol。此外，使用Desmond Maestro v11.3对11a与这三种蛋白质之间进行了分子动力学研究，以研究蛋白质-配体相互作用和蛋白质稳定性。
