Porphyrin derivatives as potent and selective blockers of neuronal Kv1 channels

Daly, Declan; Al-Sabi, Ahmed; Kinsella, Gemma K.; Nolan, Kieran; Dolly, J. Oliver

doi:10.1039/c4cc05639f

Cited by 23 publications

(25 citation statements)

References 21 publications

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“…In designing selective blockers, their size and hydrophobicity are vital criteria because, if made too small, they would enter deep into the inner pore region, which is conserved in all K + channels and, similar to 4-aminopyridine (4-AP), selectivity would be lost. Although we have reported that various substituted porphyrin derivatives are selective blockers of neuronal Kv1 channels 19 due to their phototoxicity and high molecular weights, these are nonideal therapeutic candidates. 25 However, informed by structure−activity relationships of the porphyrins and using molecular modeling, valuable pharmacophore information was realized that afforded the development of a more suitable lead structure.…”

Section: Resultsmentioning

confidence: 99%

“…23,24 We recently reported that four porphyrin derivatives with different alkyl ammonium side chains (in length and geometry) inhibit Kv1.1 and/or 1.2 channels expressed in mammalian cells. 19 Now, a new generation based on diaryldi-(2-pyrrolyl) methane (DPM) is described with various substitutions bearing alkyl ammonium side-chains, which have been screened against recombinantly generated Kv1 channels of known subunit structures. The resultant data were used to design the novel small inhibitor 2,2′-((5,5′-(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2′-carbonyl)bis(azanediyl))diethaneamine• 2HCl (8), which proved selective for Kv1.1-containing channels found in rodent demyelinated axons.…”

Section: ■ Introductionmentioning

confidence: 99%

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A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

Al-Sabi¹,

Daly²,

Hoefer³

et al. 2017

J. Med. Chem.

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K channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

Al-Sabi¹,

Daly²,

Hoefer³

et al. 2017

J. Med. Chem.

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“…The manganese porphyrin compounds 1 (Mn-porphyrin) was synthesized following the reported literature with some modifications [ 34 ]. Tetrakis (4-carboxyphenyl) porphyrin (TCPP, 94 mg) was mixed with EDCI (143 mg) and NHS (90 mg) in DMF and then stirred under nitrogen.…”

Section: Methodsmentioning

confidence: 99%

pH-responsive theranostic nanocomposites as synergistically enhancing positive and negative magnetic resonance imaging contrast agents

et al. 2018

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BackgroundThe rational design of theranostic nanoprobe to present responsive effect of therapeutic potency and enhanced diagnostic imaging in tumor milieu plays a vital role for efficient personalized cancer therapy and other biomedical applications. We aimed to afford a potential strategy to pose both T1- and T2-weighted MRI functions, and thereby realizing imaging guided drug delivery and targeted therapy.ResultsTheranostic nanocomposites Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD were fabricated and characterized, and the nanocomposites were effectively used in T1- and T2-weighted MRI and pH-responsive drug release. Fluorescent imaging also showed that the nanocomposites specifically accumulated in lung cancer cells by a receptor-mediated process, and were nontoxic to normal cells. The r2/r1 ratio was 20.6 in neutral pH 7.4, which decreased to 7.7 in acidic pH 5.0, suggesting the NCs could act as an ideal T1/T2 dual-mode contrast agent at acidic environments of tumor. For in vivo MRI, T1 and T2 relaxation was significantly accelerated to 55 and 37%, respectively, in the tumor after i.v. injection of nanocomposites.ConclusionThe synthesized nanocomposites exhibited highly sensitive MRI contrast function no matter in solution, cells or in vivo by synergistically enhancing positive and negative magnetic resonance imaging signals. The nanocomposites showed great potential for integrating imaging diagnosis and drug controlled release into one composition and providing real-time imaging with greatly enhanced diagnostic accuracy during targeted therapy. Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0350-5) contains supplementary material, which is available to authorized users.

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“…H2tcpp was prepared according to literature methods. 7 A round-bottom flask was charged with 4-carboxybenzaldehyde (1.54 g, 0.0103 mol, 1.02 equiv) and propanoic acid (50 mL). The reaction mixture was heated to 80 °C until 4-carboxybenzaldehyde was completely dissolved.…”

Section: Synthesis Of 5101520-tetrakis(4-carboxyphenyl)porphyrin (mentioning

confidence: 99%

cis-Decalin oxidation as a stereochemical probe of in-MOF versus on-MOF catalysis

et al. 2017

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Development of catalyst-controlled C-H hydroxylation could provide direct access to valuable synthetic targets, such as primary metabolites. Here, we report a new family of porous materials, comprised of 2-dimensional metalloporphyrin layers and flexible aliphatic linkers, and demonstrate C-H hydroxylation activity. We demonstrate that the stereochemistry of cis-decalin oxidation provides a useful tool for differentiating catalysis in from catalysis on porous materials, which is critical to leveraging the potential of porous materials for catalyst-controlled oxidation chemistry.

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Porphyrin derivatives as potent and selective blockers of neuronal Kv1 channels

Cited by 23 publications

References 21 publications

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

pH-responsive theranostic nanocomposites as synergistically enhancing positive and negative magnetic resonance imaging contrast agents

cis-Decalin oxidation as a stereochemical probe of in-MOF versus on-MOF catalysis

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