Unraveling Solvent and Substituent Effects in the Photodynamics of Light‐Dependent Microtubule Inhibitors for Cancer Phototherapy,Journal of Computational Chemistry

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Unraveling Solvent and Substituent Effects in the Photodynamics of Light‐Dependent Microtubule Inhibitors for Cancer Phototherapy
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2025-03-11 , DOI: 10.1002/jcc.70076
Amirhossein Bakhtiiari ₁ , Ruibin Liang ₁

Affiliation

In photopharmacology, molecular photoswitches enable light‐controlled drug activities, offering precision in targeting biomolecular functions while minimizing side effects. Photostatins (PSTs) are photoswitchable analogs of combretastatin A‐4 (CA4), designed to inhibit tubulin polymerization for cancer treatment. However, the influence of substituents and molecular environments on their photochemistry remains unclear. In this work, the cis‐to‐trans photodynamics of five PSTs (PST1 to PST5) in the vacuum and aqueous solution were simulated using the ab initio multiple spawning (AIMS) coupled with correlated multireference electronic structure calculations. Four distinct minima in the same conical intersection seam were discovered, serving as nonradiative decay channels. The aqueous environment slows photoisomerization and lowers its quantum yields and changes the structures near the conical intersection seam. Substituent position and electronegativity significantly impact the isomerization kinetics by altering energy gaps between MECIs and the S1 state at the Franck‐Condon region. These findings provide useful insights into designing next‐generation phototherapeutics for cancer.

中文翻译：

揭示用于癌症光疗的光依赖性微管抑制剂光动力学中的溶剂和取代基效应

在光药理学中，分子光开关可实现光控药物活性，在靶向生物分子功能的同时最大限度地减少副作用。光抑素（PST）是 combretastatin A-4 （CA4）的可光开关类似物，旨在抑制微管蛋白聚合以治疗癌症。然而，取代基和分子环境对其光化学的影响仍不清楚。在这项工作中，使用从头再衍生（AIMS）耦合相关的多参考电子结构计算模拟了五个 PST （PST1 到 PST5）在真空和水溶液中的顺反光动力学。在同一个圆锥形交点接缝中发现了四个不同的最小值，用作非辐射衰减通道。水性环境减慢了光异构化并降低了其量子产率，并改变了圆锥形交点接缝附近的结构。取代基位置和电负性通过改变 MECI 与 Franck-Condon 区域的 S1 状态之间的能隙来显着影响异构化动力学。这些发现为设计下一代癌症光治疗药物提供了有用的见解。

更新日期：2025-03-11

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