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The creatine transporter-1 (CRT-1/SLC6A8) maintains the uphill transport of creatine into cells against a steep concentration gradient. Cellular creatine accumulation is required to support the ATP-buffering by phosphocreatine. More than 60 compounds have been explored in the past for their ability to inhibit cellular creatine uptake, but the number of active compounds is very limited. Here, we show that all currently known inhibitors are full alternative substrates. We analyzed their structure-activity relationship for inhibition of CRT-1 to guide a rational approach to the synthesis of novel creatine transporter ligands. Measurements of both inhibition of [ 3 H]creatine uptake and transport associated currents allowed for differentiating between full and partial substrates and true inhibitors. This combined approach led to a refined understanding of the structural requirements for binding to CRT-1, which translated into the identification of three novel compounds - i.e., compound 1 (2-( N -benzylcarbamimidamido)acetic acid), MIPA572 (=carbamimidoylphenylalanine), and MIPA573 (=carbamimidoyltryptophane) that blocked CRT-1 transport, albeit with low affinity. In addition, we found two new alternative full substrates, namely MIPA574 (carbamimidoylalanine) and GiDi1257 (1-carbamimidoylazetidine-3-carboxylic acid), which was superior in affinity to all known CTR-1 ligands, and one partial substrate, namely GiDi1254 (1-carbamimidoylpiperidine-4-carboxylic acid). SIGNIFICANCE STATEMENT: The creatine transporter-1 (CRT-1) is required to maintain intracellular creatine levels. Inhibition of CRT-1 has been recently proposed as a therapeutic strategy for cancer, but pharmacological tools are scarce. In fact, all available inhibitors are alternative substrates. We tested existing and newly synthesized guanidinocarboxylic acids for CRT-1 inhibition and identified three blockers, one partial and two full substrates of CRT-1. Our results support a refined structural understanding of ligand binding to CRT-1 and provide a proof-of-principle for blockage of CRT-1., (Copyright © 2024 by The Author(s).)

We have reported a direct and stereoselective synthesis of functionalized dienoic carboxylates from the simple bicyclic lactone 1. The use of oxygen- or nitrogen-based nucleophiles in a domino allylic alkylation/4π-electrocyclic ring opening affords reliable access to dienes with interesting functionalities. Alternatively, halide substitution offers synthesis of other classes of functionalized dienoic acids. Herein, we demonstrate the utility of such dienoic products as key building blocks in various transformations as well as natural product synthesis.

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.