TTFA-Platin Conjugate: Deciphering the Therapeutic Roles of Combo-Prodrug through Evaluating Stability–Activity Relationship

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-11-29 DOI:10.1021/acs.jmedchem.4c0154510.1021/acs.jmedchem.4c01545

Megha Biswas, Kanishka Chaudhary, Swati Shree Padhi, Arka Banerjee, R. Selvi Bharathavikru, Sateesh Bandaru*, Subhra Jyoti Panda, Chandra Shekhar Purohit, Nihar Ranjan Das and Rakesh Kumar Pathak*,

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Abstract

This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. In vitro studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. In vivo studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.

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这项研究介绍了一种基于铂(II)的新型原药TTFA-Platin，它将β-二酮酸配体TTFA与铂支架整合在一起，在结构上与卡铂相似，具有介于顺铂和卡铂之间的动力学稳定性，在疗效和安全性之间取得了平衡。我们在各种生物介质中进行了一项全面的稳定性和标型研究，以了解 TTFA-Platin 的治疗效果。为了进一步验证结构与稳定性之间的关系，还合成了对照分子 TMK-铂，该分子在生物系统中的活化特性较差。针对一组癌细胞系的体外研究表明，TTFA-Platin 的药效明显高于 TMK-Platin。体内研究显示，TTFA-铂的毒性明显低于参考铂化合物。因此，利用配体微调动力学稳定性并提供治疗优势，有助于开发更有效、更安全的癌症治疗方法，解决现有疗法的局限性。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.