Pradhan Sambit, Sarker Surajit, Thilagar Pakkirisamy
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, INDIA.
J Med Chem. 2024 Nov 14;67(21):18794-18806. doi: 10.1021/acs.jmedchem.4c01113. Epub 2024 Nov 2.
The precise regulation of proteasome activity has become a focal point in current research, particularly its implications in cancer treatment. Bortezomib is used for treating multiple myeloma and is found to be ineffective against solid tumors. A spatiotemporal control over the proteasome is one of the solutions to resolve these issues using external stimuli, such as light. Thus, we designed and synthesized azobenzene-containing tripeptide vinyl sulfones , , , and , as the azobenzene moiety can impart E↔Z isomerism upon exposure to UV light. Further, the hydrophobicity of these peptides was fine-tuned by systematically varying the size of hydrophobic amino acids at the P1, P2, and P3 positions. The light-induced Z isomers of these photopeptides showed excellent cellular potency in HeLa, MCF-7, and A549 cell lines. Photopeptide with valine at the proximal position, phenylalanine at P2, and leucine at the P1 positions exhibited 19.3- and 6.6-fold cellular potency in MCF-7 and A549 cells, respectively.
蛋白酶体活性的精确调控已成为当前研究的焦点，特别是其在癌症治疗中的应用。硼替佐米用于治疗多发性骨髓瘤，但对实体瘤无效。通过外部刺激（如光）对蛋白酶体进行时空控制是解决这些问题的方法之一。因此，我们设计并合成了含有偶氮苯的三肽乙烯砜 、 、 、和 ，因为偶氮苯部分在暴露于紫外光时可以赋予 E↔Z 异构化。此外，通过系统改变 P1、P2 和 P3 位置疏水性氨基酸的大小来精细调整这些肽的疏水性。这些光肽的光诱导 Z 异构体在 HeLa、MCF-7 和 A549 细胞系中表现出优异的细胞效力。带有缬氨酸的光肽 在近端位置、苯丙氨酸在 P2 位置和亮氨酸在 P1 位置在 MCF-7 和 A549 细胞中分别表现出 19.3 倍和 6.6 倍的细胞效力。
