2.B.21 The ortho-Phenylenediamine-bis-Urea Derivative Anion Transporter (oPDA-U) Family

Fluorinated ortho-phenylenediamine-bis-urea derivatives have been shown to function as highly effective transmembrane anion antiporters with the most active transporters rivalling the transport efficacy of the natural anion transporter, prodigiosin (2.B.20), for bicarbonate (Karagiannidis et al. 2014; Gale 2011). In fact, ortho-phenylene bisureas provide a successful motif for developing anion receptors. Davis, Sheppard, Gale and co-workers studied derivatives 75a–c and 76a–d (see figure below), exploring different substitution patterns of the central aromatic scaffold (Dias et al. 2018; Li et al. 2019). Employing the halide-sensitive fluorescent dye lucigenin, the anion transport activities of these compounds were explored in POPC/cholesterol LUVs. The effect of pre-incorporating the compound into the membrane or adding it externally was assayed. The most effective carrier in all assays was found to be 75a, bearing a difluorinated central aromatic scaffold. The study of the pre-incorporated compounds also highlighted the importance of deliverability of the compounds in order to attain significant activity. Thus, within the ester appended 76a–d series, compound 76d bearing a lipophilic n-octyl chain increased its transport activity when pre-incorporated in the membrane. Pre-incorporation is not possible in cellular assays, and when these compounds were assayed using Fischer rat thyroid cells expressing the halide sensor YFP-H148Q/I152L (YFP-FRT cells), similar results to those observed in vesicles when added externally were observed. Compound 75a was shown to promote iodide internalisation. This also suggested the opportunity to develop drug delivery methods to explore the potential of the most lipophilic derivatives (Davis et al. 2020).

Fig. 54 ortho-Phenylene bisureas 75a–c and 76a–d.

 

References:

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]

Dias, C.M., H. Li, H. Valkenier, L.E. Karagiannidis, P.A. Gale, D.N. Sheppard, and A.P. Davis. (2018). Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes. Org Biomol Chem 16: 1083-1087.

Gale, P.A. (2011). From anion receptors to transporters. Acc Chem Res 44: 216-226.

Karagiannidis, L.E., C.J. Haynes, K.J. Holder, I.L. Kirby, S.J. Moore, N.J. Wells, and P.A. Gale. (2014). Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas. Chem Commun (Camb) 50: 12050-12053.

Li, H., H. Valkenier, A.G. Thorne, C.M. Dias, J.A. Cooper, M. Kieffer, N. Busschaert, P.A. Gale, D.N. Sheppard, and A.P. Davis. (2019). Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs. Chem Sci 10: 9663-9672.