Tambjamine alkaloids and related synthetic analogs: efficient transmembrane anion transporters

Hernández, Paulina Iglesias; Moreno, Daniel; Javier, Anatalia Araujo; Torroba, Tomás; Pérez-Tomás, Ricardo; Quesada, Roberto

doi:10.1039/c1cc11300c

Cited by 76 publications

(54 citation statements)

References 38 publications

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“…21 By contrast, currently no anionophore has been identified with strong Cl À > H + /OH À selectivity. 22 Indeed, prodigiosin, 14,15 and some of the most powerful synthetic anionophores, [23][24][25][26][27] have been shown to uncouple vacuolar type H + -ATPase (V-ATPase) and neutralize acidic cellular organelles (such as the Golgi apparatus, lysosomes, and endosomes) by facilitating H + /Cl À symport or Cl À /OH À antiport through organelle membranes. Monensin is also known to exhibit this neutralization effect by promoting Na + /H + antiport through organelle membranes.…”

Section: Introductionmentioning

confidence: 99%

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Judd

Howe

et al. 2016

Chem

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160

202

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Synthetic anion transporters can facilitate H + transport via deprotonation, or OH À transport via hydrogen bonding to OH À , thus allowing dissipation of transmembrane pH gradients, an undesired side-effect for biomedical applications as Cl À ionophores. To address this limitation, Gale and colleagues have developed two anionophores that show high Cl À > H + /OH À selectivity. Preliminary cellular studies support the biological relevance of the selectivity.

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Section: Introductionmentioning

confidence: 99%

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Judd

Howe

et al. 2016

Chem

Self Cite

160

202

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“…We have recently synthesized novel synthetic tambjamine analogues bearing aromatic substituents in the enamine moiety, as well as explored different substitution patterns on characteristic alkoxy group of the central pyrrole ring. These compounds proved to be very efficient anion exchangers in liposome models, promoting both chloride and bicarbonate transport [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Rodilla

Korrodi‐Gregório

Hernando

et al. 2017

Biochemical Pharmacology

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Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with different mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favors cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as a novel antitumor drugs. Despite this, little is known about the implications of pH deregulation and homeostasis imbalance triggered by ionophores at the cellular level. In this work, we deeply analyze for the first time the anticancer effects of tambjamine analogues, a group of highly effective anion selective ionophores, at the cellular and molecular level. First, their effects on cell viability were determined in several lung cancer cell lines and patient-derived cancer stem cells, demonstrating their potent cytotoxic effects. Then, we have characterized the induced lysosomal deacidification, as well as, the massive cytoplasmic vacuolization observed after treatment with these compounds, which is consistent with mitochondrial swelling. Finally, the activation of several proteins involved in stress response, autophagy and apoptosis was also detected, although necrosis was the main mechanism of cell death induced.Altogether, these evidences suggest that tambjamine analogues provoke an imbalance in cellular ion homeostasis that triggers mitochondrial dysfunction and lysosomal deacidification leading to a potent cytotoxic effect through necrosis in lung cancer cell lines and cancer stem cells.

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“…They contain bipyrrole core and, like other natural and semi- synthetic acyclic anion receptors have received increasing attention as anion carriers in recent years [97,99]. Tambjamines are typically easier to prepare than the prodigiosins and generally possess higher p K a values (i.e., p K a ≈ 10 vs. 7.2, for tambjamines and prodigiosins, respectively); thus, unlike prodigiosins, tambjamines remain largely protonated at physiological pH.…”

Section: Prodigiosin- Tambjamine- and Perenosin-based Anion Recepmentioning

confidence: 99%

“…Quesada and coworkers described transmembrane anion transport studies of the tambjamine alkaloid derivative 44a and reported that these compounds are potent anion transporters capable of effecting NO 3 − /Cl − and HCO 3 /Cl − exchange in liposomes at low concentrations [99]. The lower intracellular pH levels observed in vitro correlated with antitumor activity in the human melanoma (A375) and human mammary epithelial (MCF-10A) cell lines.…”

Section: Prodigiosin- Tambjamine- and Perenosin-based Anion Recepmentioning

confidence: 99%

Pyrrole N–H anion complexes

Vargas‐Zúñiga

Sessler

2017

Coordination Chemistry Reviews

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Synthetic pyrrole-based anion receptors date back to the 1990s. They have been extensively developed in the context of macrocyclic systems as expanded porphyrins and calixpyrroles, and related systems. The chemistry of open-chain pyrrolic systems is, in many respects, no less venerable. It also has more direct analogy to naturally occurring pyrrole-based anion binding motifs. However, it has not been the subject of a comprehensive review. Presented herein is a summary of efforts devoted to the creation of de novo pyrrole-based receptors, as well as the anion recognition chemistry of naturally occurring pyrrolic systems as prodigiosins and their synthetic analogues.

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Tambjamine alkaloids and related synthetic analogs: efficient transmembrane anion transporters

Abstract: The tambjamine alkaloids and related synthetic analogs are potent transmembrane anion tranporters promoting bicarbonate/chloride exchange in model phospholipid liposomes and discharging pH gradients in living cells.

Cited by 76 publications

References 38 publications

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Pyrrole N–H anion complexes

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