Design, Synthesis, and Evaluation of Sodium Channel Blockers with Anti-invasive Activities in Medullary Thyroid Cancer
This letter describes the structure-activity relationship studies of a voltage-gated sodium channel (VGSC) blocker <b>SV188</b> guided by its docking model in the lacosamide binding site of Na<sub>V</sub>1.7. Seventeen analogs of <b>SV188</b> were designed, synthesized, and evaluated for whole cell <i>I</i> <sub>Na</sub> blockade and cytotoxicity using metastatic medullary thyroid cancer cell line MZ-CRC-1. Three analogs exhibited improved <i>I</i> <sub>Na</sub> blockade compared to <b>SV188</b>. Thirteen analogs showed reduced cytotoxicity compared to <b>SV188</b>. 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 <b>SV188</b>. The most promising lead compound <b>IIB7</b> showed no cytotoxicity to MZ-CRC-1 cells up to 100 μM and inhibited VGSC-mediated cell invasion by 71% at 15 μM.
Authors
- Sadanandan E. Velu (ORCID: https://orcid.org/0000-0002-0342-2378)
- Juan Carlos Gómora (ORCID: https://orcid.org/0000-0002-9871-1307)
- Shilpa Dutta (ORCID: https://orcid.org/0000-0002-9768-1935)
- Polani B. Ramesh Babu (ORCID: https://orcid.org/0000-0003-3416-7186)
- Renata Jaskula‐Sztul
- Osbaldo Lopez‐Charcas (ORCID: https://orcid.org/0000-0002-5080-8310)
- Piyasuda Pukkanasut (ORCID: https://orcid.org/0000-0002-0726-3060)
- Tonantzin Guadalupe Anguheven‐Ledezma (ORCID: https://orcid.org/0009-0005-8029-6167)
- Jason Whitt
Institutions
- University of Alabama at Birmingham (US)
- Instituto Nacional de Cardiología (MX)
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00576
- Citations
- 1
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Institutes of Health
- Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México