Design, Synthesis, and Evaluation of Sodium Channel Blockers with Anti-invasive Activities in Medullary Thyroid Cancer.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 eCollection Date: 2025-05-08 DOI:10.1021/acsmedchemlett.4c00576

Piyasuda Pukkanasut, Shilpa Dutta, Jason Whitt, Parvathy Babu, Osbaldo Lopez-Charcas, Tonantzin Guadalupe Anguheven-Ledezma, Juan Carlos Gomora, Renata Jaskula-Sztul, Sadanandan E Velu

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引用次数: 0

Abstract

This letter describes the structure-activity relationship studies of a voltage-gated sodium channel (VGSC) blocker SV188 guided by its docking model in the lacosamide binding site of Na_V1.7. Seventeen analogs of SV188 were designed, synthesized, and evaluated for whole cell I _Na blockade and cytotoxicity using metastatic medullary thyroid cancer cell line MZ-CRC-1. Three analogs exhibited improved I _Na blockade compared to SV188. Thirteen analogs showed reduced cytotoxicity compared to SV188. Three selected compounds were further evaluated for their cell invasion inhibition activities. All three compounds displayed cell invasion inhibitory activities that were better than those of SV188. The most promising lead compound IIB7 showed no cytotoxicity to MZ-CRC-1 cells up to 100 μM and inhibited VGSC-mediated cell invasion by 71% at 15 μM.

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抗甲状腺髓样癌侵袭性钠通道阻滞剂的设计、合成和评价。

本文描述了电压门控钠通道（VGSC）阻滞剂SV188在NaV1.7 lacosamide结合位点对接模型指导下的构效关系研究。设计、合成了17个SV188类似物，并对转移性甲状腺髓样癌细胞MZ-CRC-1进行了全细胞I Na阻断和细胞毒性评价。与SV188相比，三个类似物表现出更好的I Na阻断。与SV188相比，13个类似物的细胞毒性降低。进一步评价了三种化合物的细胞侵袭抑制活性。3种化合物的细胞侵袭抑制活性均优于SV188。最有希望的先导化合物IIB7在100 μM范围内对MZ-CRC-1细胞无细胞毒性，在15 μM范围内对vgsc介导的细胞侵袭有71%的抑制作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.