2.B.44.  The Synthetic Indole-based Perenosin (SIP) Family 

Prodigiosin (TC# 2.B.20) is one of the most potent anion transporters. Inspired by the structure of this natural product, Jowett et al. 2017 designed and synthesised a new class of H+/Cl- cotransporters named 'perenosins'. The described a library of indole-based perenosins and their anion transport properties. The new transporters showed superior transmembrane transport efficiency when compared to other indole-based transporters, due to favourable encapsulating effects from the substituents on the perenosin backbone. The compounds function as 'strict' HCl cotransporters. Cell viability studies showed that some compounds specifically trigger late-onset cell death after 72 h with a unique correlation to the position of alkyl chains on the perenosins. A combination of cell cycle arrest and apoptosis was responsible for the observed decrease in cell viability (Jowett et al. 2017).

Indole-based perenosins 112 were prepared and tested by Jowett et al. 2017 (see figure below). These derivatives are excellent anion transporters with ISE assay-determined EC50 values as low as 0.0043 mol% for 112f. Mechanistic investigations demonstrated that this class of compounds function predominantly by electroneutral H+/Cl symport. Cell viability studies indicated a selective viability decrease in human breast adenocarcinoma cell line (MDA-MB-231) over the other cell lines. These compounds exhibited a distinctive late onset of cytotoxicity. Thus, whereas IC50 at 72 h in the range of 10 μM was calculated, no significant decrease of viability was observed for these compounds after 24 h for concentrations up to 100 μM. Annexin V assays indicated apoptotic processes as well as cell cycle arrest as cell death mechanisms (Davis et al. 2020).

 Indole-based perenosins 112a–j.




Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print]

Jowett, L.A., E.N.W. Howe, V. Soto-Cerrato, W. Van Rossom, R. Pérez-Tomás, and P.A. Gale. (2017). Indole-based perenosins as highly potent HCl transporters and potential anti-cancer agents. Sci Rep 7: 9397.