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Mar. Drugs 2018, 16(12), 475; https://doi.org/10.3390/md16120475

Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers

Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane, Qld 4072, Australia
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Received: 8 November 2018 / Revised: 21 November 2018 / Accepted: 26 November 2018 / Published: 28 November 2018
(This article belongs to the Special Issue Synthesis of marine natural products and analogues)
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Abstract

T-type calcium channel (CaV3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson’s disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved CaV3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual CaV3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two CaV3.2 (2, IC50 = 18.24 µM; 3, IC50 = 6.59 µM) and CaV3.3 (2, IC50 = 7.71 µM; 3, IC50 = 3.81 µM) selective blockers using a FLIPR cell-based assay measuring CaV3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of CaV3.1 activated current (2, IC50 = 5.60 µM; 3, IC50 = 9.91 µM), suggesting their state-dependent block is subtype specific. View Full-Text
Keywords: CaV3.x blockers; bisindole alkaloid; marine fungal product; pseudellone C CaV3.x blockers; bisindole alkaloid; marine fungal product; pseudellone C
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Wang, D.; Neupane, P.; Ragnarsson, L.; Capon, R.J.; Lewis, R.J. Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers. Mar. Drugs 2018, 16, 475.

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