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The Alanine, Serine, and Cysteine Transporter 2 (ASCT2) transports glutamine into cells and is upregulated in many cancers. Attachment to glutamine to enable ASCT2 to transport anticancer agents into cells has been proposed, but the impact of such modifications is a critical determinant of the potential of this strategy. Transport via ASCT2 of two glutamine analogues modified in ways that reflect possible mechanisms for attaching anticancer agents was studied. The aim was to determine if the modification of glutamine interferes with its transport via ASCT2 and thereby establish whether the conjugation of drugs to glutamine can facilitate the accumulation of anticancer drugs in cancer cells. L-theanine and a glutamine derivative modified at the carboxylate (7) were applied to Xenopus laevis oocytes expressing ASCT2. Two-electrode voltage clamp electrophysiology was used to measure substrate-elicited currents over a range of membrane potentials. Compound 7 was identified as neither a substrate nor an inhibitor while L-theanine was identified as an inhibitor of ASCT2. Thus, modification of glutamine in these ways prevents it from acting as a substrate and suggests that ASCT2 may not be a suitable target for delivery of anticancer drugs attached via either the carboxylate or side chain positions., (© 2024 Wiley‐VCH GmbH.)

Complexes incorporating a threading anthraquinone intercalator with pyrrole lexitropsin and platinum(II) moieties attached were developed with the goal of generating novel DNA binding modes, including the targeting of AT-rich regions in order to have high cytotoxicities. The binding of the complexes to DNA has been investigated and profiles surprisingly similar to that for cisplatin were observed; the profiles were different to those for a complex lacking the pyrrole lexitropsin component. The lack of selective binding to AT-rich regions suggests the platinum binding was dominating the sequence selectivity, and is consistent with the pyrrole lexitropsin slowing intercalation. The DNA unwinding profiles following platinum binding were evaluated by gel electrophoresis and suggested that intercalation and platinum binding were both occurring.