Zaman Hina, Saeed Aamer, Azam Uzma, Shabir Ghulam, Irfan Madiha, Farag Basant, El-Seedi Hesham R
Department of Chemistry, Quaid-I-Azam University Islamabad 45320 Pakistan
Institute of Chemistry, Khawaja Fareed University of Engineering and Information Technology Rahim Yar Khan 64200 Pakistan.
RSC Adv. 2025 Sep 2;15(38):31548-31563. doi: 10.1039/d5ra05647k. eCollection 2025 Aug 29.
Cancer continues to be a major global health challenge, necessitating the ongoing development of novel small-molecule therapeutics that can selectively target DNA and disrupt cancer cell proliferation. In this study we report the synthesis and characterization of novel guanidine derivatives (7a-j). Their DNA-binding potential was assessed through electronic absorption spectroscopy, revealing characteristic hypochromic shifts indicative of minor groove-binding interactions with salmon sperm DNA (SS-DNA). Among the series, 4-Me, 4-Br-substituted compound (7i) exhibited the highest binding constant ( = 3.49 × 10 ± 0.04 M at 298 K), comparable to that of the reference groove binder, cabozantinib ( = 5.79 × 10 M). The negative Gibbs free energy change (Δ = -31.61 kJ mol) confirmed the spontaneity and thermodynamic stability of the binding interaction. Molecular docking studies further supported these experimental findings, with compound (7i) displaying a favorable docking score of -8.9 kcal mol and forming hydrogen bonding and hydrophobic interactions within the DNA minor groove. Additionally, DFT calculations and ADMET predictions provided insights into the electronic features and pharmacokinetic attributes of novel guanidine derivatives (7a-j), establishing DNA binding as a mechanistic foundation and reinforcing their rationale for future evaluation in anticancer drug discovery.
癌症仍然是一项重大的全球健康挑战，因此需要持续研发能够选择性靶向DNA并扰乱癌细胞增殖的新型小分子疗法。在本研究中，我们报告了新型胍衍生物（7a-j）的合成与表征。通过电子吸收光谱法评估了它们与DNA的结合潜力，结果显示出特征性的减色位移，表明其与鲑鱼精DNA（SS-DNA）存在小沟结合相互作用。在该系列化合物中，4-甲基、4-溴取代的化合物（7i）表现出最高的结合常数（298 K时K = 3.49 × 10 ± 0.04 M），与参考沟结合剂卡博替尼（K = 5.79 × 10 M）相当。吉布斯自由能变化为负值（Δ = -31.61 kJ mol），证实了结合相互作用的自发性和热力学稳定性。分子对接研究进一步支持了这些实验结果，化合物（7i）的对接分数为-8.9 kcal mol，在DNA小沟内形成了氢键和疏水相互作用。此外，密度泛函理论计算和ADMET预测为新型胍衍生物（7a-j）的电子特征和药代动力学属性提供了见解，将DNA结合确立为一种作用机制基础，并强化了其在抗癌药物发现中进行未来评估的理论依据。
