Menon Vijay, Katner Samantha J, Lee Daniel E, Peterson Erica J, Koblinski Jennifer E, Farrell Nicholas P
Massey Cancer Center, Virginia Commonwealth University, VA 23298, USA; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040, USA.
Department of Chemistry, Virginia Commonwealth University, VA 23284, USA; Massey Cancer Center, Virginia Commonwealth University, VA 23298, USA; Department of Biochemistry, Chemistry, and Geology, Minnesota State University, Mankato, MN 56001, USA.
J Inorg Biochem. 2024 Mar;252:112475. doi: 10.1016/j.jinorgbio.2023.112475. Epub 2023 Dec 29.
Utilizing isoquinoline as a carrier ligand, we have evaluated the reactivity of selected trans‑platinum planar amine (TPA) carboxylate compounds by varying the leaving carboxylate group (acetate, hydroxyacetate, and lactate) in an effort to optimize the cytotoxic and metabolic efficiency. To measure the pharmacological properties of these compounds, a combination of systematic biophysical and biological studies were carried out mainly involving substitution reaction with NAM (N-acetyl-methionine), effects on DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects. TPA compounds showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum, while displaying a distinct micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle. Monitoring the TPA compounds with NAM suggests the following trend for the reactivity: hydroxyacetate > lactate > acetate. The same trend was seen for the cytotoxicity in tumor cells and DNA binding, while the rate of drug inactivation/protein binding in cells was not significantly different among these leaving groups. Thus, our results show superior cellular efficacy of TPA compounds and distinct micromolar cytotoxic activities different than cisplatin. Moreover, we found the TPA compounds had prolonged survival and decreased tumor burden compared to the control mice in a relevant human ovarian cancer mouse model with A2780 cells expressing luciferase. Therefore, we propose that further optimization of the basic TPA structure can give further enhanced in vivo activity and may eventually be translated into the development of clinically relevant non-traditional platinum drugs.
我们以异喹啉作为载体配体，通过改变离去的羧酸根基团（乙酸根、羟基乙酸根和乳酸根）来评估选定的反式铂平面胺（TPA）羧酸盐化合物的反应活性，以优化其细胞毒性和代谢效率。为了测定这些化合物的药理学性质，我们进行了系统的生物物理和生物学研究，主要包括与N-乙酰甲硫氨酸（NAM）的取代反应、对DNA结构扰动的影响、细胞毒性、细胞摄取、代谢稳定性以及细胞周期效应。TPA化合物在与血清预孵育后，细胞毒性效力损失最小，且优于顺铂，同时表现出明显的微摩尔级细胞毒性活性，DNA结合最少且细胞周期未改变。用NAM监测TPA化合物表明其反应活性有以下趋势：羟基乙酸根＞乳酸根＞乙酸根。在肿瘤细胞的细胞毒性和DNA结合方面也观察到相同趋势，而这些离去基团在细胞中的药物失活/蛋白质结合速率没有显著差异。因此，我们的结果表明TPA化合物具有优异的细胞效能以及与顺铂不同的明显微摩尔级细胞毒性活性。此外，在表达荧光素酶的A2780细胞的相关人卵巢癌小鼠模型中，我们发现与对照小鼠相比，TPA化合物能延长生存期并减轻肿瘤负担。因此，我们建议进一步优化基本的TPA结构可以进一步增强体内活性，并最终可能转化为临床相关的非传统铂类药物的开发。
