Co-transport of H+/Cl– by a synthetic prodigiosin mimic

Gale, Philip A.; Light, Mark E.; McNally, Beth A.; Navakhun, Korakot; Sliwinski, Kate E; Smith, Bradley D.

doi:10.1039/b503906a

Cited by 130 publications

(73 citation statements)

References 25 publications

(10 reference statements)

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“…The data in Figure 4 shows that the background proton efflux rate is quite substantial due to the large pH gradient. This feature has been observed previously and is discussed in reference 4 . Hydrogen bonded dimer of the HCl complex of 3 with selected atom labelling.…”

Section: Acknowledgmentssupporting

confidence: 69%

“…3 Recently, we demonstrated that compound 2 is a weak chloride receptor at neutral pH but when protonated shows a significantly enhanced chloride binding affinity. 4 Transport studies showed that 2 functions as an HCl co-transporter in vesicles, and that transport was accelerated by the presence of a pH gradient. More recently, J.T.…”

Section: Introductionmentioning

confidence: 99%

“…A chloride selective electrode was used to detect chloride release from the vesicles. 4 Under neutral conditions, only compound 3 was an effective chloride transporter, with efflux rate slightly inhibited by the presence of cholesterol (Fig 2). Structurally, 3 and 4 only vary by a single nitrogen atom but their transport activities are quite different, lending support to the concept of enhanced transport by a receptor (3) that has a more preorganised and convergent binding pocket.…”

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confidence: 99%

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Conformational control of HCl co-transporter: imidazole functionalised isophthalamide vs. 2,6-dicarboxamidopyridine

et al. 2007

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Replacement of the central isophthalamide core in a synthetic HCl receptor, with a 2,6-dicarboxamidopyridine, leads to a more preorganized molecular structure that exhibits higher chloride affinity and membrane transport flux.There is currently strong interest in the design of synthetic membrane transporters for anions. 1 The goal of our collaborative research programme is to develop HCl co-transport systems. These compounds are designed to act as functional mimics of the prodigiosin family of natural products (e.g., 1) which have been shown to promote the co-transport of H + /Cl − across bilayer membranes. 2 These natural products exhibit a range of potentially useful biological activities, including immunosuppression, induction of tumor cell apoptosis, and toxicity against bacteria, protozoa, fungi and malaria parasite. 3 Recently, we demonstrated that compound 2 is a weak chloride receptor at neutral pH but when protonated shows a significantly enhanced chloride binding affinity. 4 Transport studies showed that 2 functions as an HCl co-transporter in vesicles, and that transport was accelerated by the presence of a pH gradient. More recently, J.T. Davis, Gale, Quesada and co-workers reported that an isophthalamide-derived carrier, with hydroxyl groups in the 4-and 6-positions, functions as a very efficient chloride transporter across vesicle membranes. 5 This functionalised system is more highly preorganised than a simple isophthalamide due to the presence of intramolecular hydrogen bonds. Furthermore, the internal hydrogen bonds decrease the molecular polarity. We decided to test the generality of this preorganisation concept and evaluate a series of putative HCl co-transporters 3 and 4 that contain either an isophthalamide or 2,6-dicarboxamide core and a pendant methylimidazole ring. As with 1 and 2, compounds 3 and 4 contain two hydrogen bond donor groups and a basic site. However, the pyridyl analogue 3 was expected to possess a higher degree of preorganisation than the isophthalamide 4, due to the well-known propensity of pyridine-2,6-dicarboxamides to adopt a syn-syn bis(amide) conformation that creates a convergent hydrogen bonding pocket. 6 We also prepared and evaluated the negative control compound 5 which lacks the basic imidazole ring. Compound 3 was synthesized by conversion of 6-(methoxycarbonyl)pyridine-2-carboxylic acid 7 to the acid chloride, followed by addition of (1-methyl-1H-imidazol-2-yl) methanamine8, subsequent saponification of the methyl ester, conversion to the acid chloride and finally addition of 4-butylaniline to afford compound 3 (47% yield). Compound 4 was obtained by addition of one equivalent of 4-butylaniline to N 1 ,N 3 -bis(2-mercaptothiazolides)-isophthalamide 9 followed by the addition of (1-methyl-1H-imidazol-2-yl)methanamine8 to afford 4 (yield 18%).The anion binding affinities of receptors 3 and 4 were studied by standard 1 H NMR titration techniques with tetrabutylammonium chloride in DMSO-d 6 , and the stability constants determined using EQNMR computer pro...

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Section: Acknowledgmentssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Conformational control of HCl co-transporter: imidazole functionalised isophthalamide vs. 2,6-dicarboxamidopyridine

et al. 2007

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“…7,8 Despite the obvious importance of transmembrane bicarbonate transport, there have been no reports, to the best of our knowledge, of "small" molecules that are capable of promoting bicarbonate transport across lipid membranes, in contradistinction to the growing body of work on chloride and HCl transport across phospholipid vesicle membranes. [9][10][11][12][13][14][15] Phospholipid vesicles have been extensively investigated because of their usefulness as models for biological membranes. Unilamellar vesicles of a specific size are easily produced with control of the entrapped solution.…”

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Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

et al. 2009

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“…This family of natural products exhibits promising anticancer, antimicrobial and immunosuppressive activities. [2][3][4][5] Published work, [2,[6][7][8][9] including some from commercial ventures, demonstrates that interest in the anticancer activities of prodigiosin analogues is currently high. While biological studies on synthetic prodigiosin derivatives (prodigiosenes) [10] showed that the methoxy group in ring B is essential for anticancer activity, [11,12] fine tuning of the structure through derivatisation of the A and C rings is somewhat tolerated.…”

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Amido‐Functionalised Prodigiosenes: Synthesis and Anticancer Properties

2009

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Co-transport of H+/Cl– by a synthetic prodigiosin mimic

Abstract: An amidopyrrole with appended imidazole group can bind and co-transport H+/Cl- across vesicle membranes much more effectively than an analogue with an appended pyridyl group.

Cited by 130 publications

References 25 publications

Conformational control of HCl co-transporter: imidazole functionalised isophthalamide vs. 2,6-dicarboxamidopyridine

Conformational control of HCl co-transporter: imidazole functionalised isophthalamide vs. 2,6-dicarboxamidopyridine

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Amido‐Functionalised Prodigiosenes: Synthesis and Anticancer Properties

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