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

Philip A. Gale, Mark E. Light, Beth McNally, Korakot Navakhun, Kate E. Sliwinski, Bradley D. Smith
2005 Chemical Communications  
An amidopyrrole with appended imidazole group can bind and co-transport H + /Clacross vesicle membranes much more effectively than an analogue with an appended pyridyl group. A number of membrane-bound cellular compartments, such as the organelles of the biosynthetic and endocytic pathways, maintain acidic interiors that are crucial for organelle function and cell survival. There is literature evidence that connects abnormal changes in organelle steady-state pH with the pathology of several
more » ... logy of several diseases. 1 In addition, drug-resistant tumor cells are known to have organelles that are unusually acidic, and chemical agents that deacidify these organelles can restore drug-sensitivity. 2,3 Deacidification of organelles can be induced by treatment with weak bases, ionophores, or v-type ATPase inhibtors. A subclass of the weak bases are compounds that act as H + /Clco-transporters. The best known examples are the prodigiosins, a family of naturally occurring pyrrole alkaloids, 4 produced by microorganisms such as Streptomyces and Serratia. 5,6 They have the general structure 1, and exhibit a range of potentially useful biological activities, including immunosuppression, induction of tumor cell apoptosis, and toxicity against bacteria, protozoa, fungi and malaria parasite. 7,8 There is clear evidence that prodigiosins promote the co-transport of H + /Clacross bilayer membranes. 9-13 However, it is not conclusive which, if any, of the biological activities are directly due to organelle deacidification. For example, the prodigiosins are also known to affect mitogen-activated kinase signalling cascades, 14 and to facilitate double-strand DNA cleavage in the presence of Cu(II) and O 2 . 15
doi:10.1039/b503906a pmid:16041412 fatcat:6utq5o5ilvgr5h7b5iah6aesei