Targeting monocarboxylate transporter 1 with a copper-chelating coumarin-based bioconjugate: Synthesis and characterization

Volume 275, February 2026, 113130

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Monocarboxylate Transporter 1 (MCT1) plays a crucial role in cancer metabolism and it is a promising target for theranostics.

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A new bioconjugate (LCPn) combining a coumarin-based MCT1-targeting unit with a copper chelator is designed and synthesized.

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LCPn forms stable 1:1 complexes with Cu(II) and Zn(II)[CuLCPn]+ shows quasi-reversible redox behavior, ideal for radiolabeling and imaging.

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Docking and cell assays confirmed LCPn ’s high affinity for MCT1 and lactate uptake’s inhibition in prostate cancer cells.

Abstract

Monocarboxylate Transporters (MCTs), particularly MCT1, are increasingly recognized as key regulators of cancer metabolism, facilitating lactate exchange and contributing to tumor aggressiveness. Their overexpression in various malignancies makes them attractive targets for both therapeutic and diagnostic strategies. In this study, we report the design, synthesis, and comprehensive characterization of a novel chimeric bioconjugate, LCPn, integrating a coumarin-based MCT1-targeting moiety with a TACN(1,4,7-triazacyclononane)-containing chelator, optimized for copper radioisotope binding. The synthetic route was refined through strategic modifications, including mono-Boc (tert-butyloxycarbonyl) protecting group protection of the macrocycle and efficient SN2-type coupling via thionyl chloride activation. Structural confirmation was achieved through nuclear magnetic resonance and mass spectrometry. Five protonation constants were determined for LCPn, reflecting contributions from both the chelator and targeting domains. Complexation studies with Cu2+ and Zn2+ confirmed the formation of stable 1:1 metal-to-ligand complexes, while cyclic voltammetry studies indicated a quasi-reversible redox behaviour upon Cu2+ to Cu+ reduction. Docking simulations and cell-based assays demonstrated that the coumarin-based targeting moiety exhibits high affinity for MCT1 and effectively inhibits lactate uptake in prostate cancer models. These findings underscore the dual functionality of LCPn as a selective MCT1-targeting agent and a robust copper-chelating platform, paving the way for future theranostics applications in oncology exploiting inorganic bioconjugates.

Graphical abstractA novel bioconjugate (LCPn) combining a coumarin-based Monocarboxylate Transporter 1 (MCT-1)-targeting unit with a copper-binding chelator has been designed and synthesized. LCPn is a selective MCT1-targeting agent and a robust copper-chelating platform for theranostics. Unlabelled Image