Aromatic Guanidine Research Articles

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD-ligand interactions.

The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named "Hv1 Inhibitor Flexibles" (HIFs), consist of two "prongs," an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.

Aromatic guanidines as highly active binary catalytic systems for the fixation of CO2 into cyclic carbonates under mild conditions

The formation of hydrogen bonding causes a considerable decrease in the reaction temperature and CO2 pressure used in this process.

Exploiting Π-Stacking Interactions to Improve Inhibition of the Hv1 Channel by Aromatic Guanidine Derivatives

The human Hv1 voltage-gated proton channel is an emerging drug target for cancer and stroke. It resides on the cell plasma membrane and endocytic compartments where it mediates outward proton movement and regulates the activity of NOX enzymes. The channel consists of two identical subunits which gate cooperatively. Each subunit contains a proton-conducting voltage-sensing domain (VSD) which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). We have previously found that mutating the Hv1 residue F150 to an alanine increases the 2GBI binding affinity more than two orders of magnitude. Understanding how 2GBI and its analogs interact with Hv1 F150A is critical to the design of more effective inhibitors for the wild type channel. We hypothesized that the binding of 2GBI to the mutant channel is stabilized by π-stacking interactions between the inhibitor and aromatic residues located in the core of the VSD. We tested this hypothesis using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated aromatic amino acids via nonsense suppression methodology. Considering their proximity to the 2GBI binding site, we investigated residues F149 and F182. We found that F182 does contribute to 2GBI binding via π-stacking interactions while F149 does not. To test whether strengthening the π-stacking interactions can lead to more potent inhibitors, we measured the binding affinities of a series of aromatic guanidine derivatives carrying an increasing number of fluorine substituents. We discuss the results based on our understanding of the mechanism of channel block by these compounds. Possible alterations of the inhibitor structure to improve binding to the wild type channel are also discussed.

Oxygen Activation by Copper Complexes with an Aromatic Bis(guanidine) Ligand

Combining the new aromatic bis(guanidine) ligand bis(tetramethylguanidino)toluene (TMG2tol) and different copper salts led to four new complexes. The molecular structures were analysed by X‐ray diffraction. Three of the complexes are active in biomimetic activation of oxygen. It is the first time a bis‐µ‐oxido species of an aromatic guanidine copper complex is analysed by Raman and UV/Vis spectroscopy. The formation and decay of the bis(µ‐oxido)dicopper species were investigated at low temperatures up to 273 K by UV/Vis spectroscopy with a stopped‐flow setup. The results showed that the Cu2O2 intermediate of an aromatic guanidine–copper complex decays much faster than most known bis(guanidine) complexes. Moreover, natural bond orbital (NBO) analyses revealed that the aromatic guanidine is the stronger donor compared to the aliphatic one.

Zinc Chloride Complexes with Aliphatic and Aromatic Guanidine Hybrid Ligands and Their Activity in the Ring‐Opening Polymerisation of d,l‐Lactide

The synthesis of the new hybrid guanidine ligands DMEGdmap, DMEGdeae, TMGdmab, DMEGdmab, TMGdeab and DMEGdeab is reported. These ligands were combined with zinc chloride, and the six obtained new complexes were structurally characterised by X‐ray crystallography and NMR spectroscopy. Further six new zinc chloride complexes were obtained from the hybrid guanidine ligands TMGdmae, DMEGdmae, TMGdeae, TMGdmap, TMGdeap and TEGdeap. Each of the twelve complexes possesses a tetrahedral coordination geometry. The donor situation between guanidine and amine donors was evaluated by use of density functional theory. These complexes show robust activity in the melt polymerisation of technical unsublimed lactide. For selected complexes kinetic polymerisation experiments were performed; these showed first‐order behavior. The end‐group was established by NMR spectroscopy.

Two unprecedented aromatic guanidines supramolecular chains self-assembled by hydrogen bonding interaction

Two aromatic guanidine derivatives, C6H5N=C(NHCy)2 (1), (n-TBA)C6H5NHC(NHCy)2Mo2O7 (2) (Cy=cyclohexyl), were synthetized with high yields. Both of them self-assembled into supramolecules via H-bond interactions. Single crystal XRD indicated that crystal 1 showed helix chains combining pseudo four-fold and pseudo six-fold symmetries, while crystal 2 presented ladder chains with alternate ring structures. In this paper, a novel way to design ladder-like supramolecular chains from helix chains was presented, using POMs (polyoxometalates) to provide protons to help assembly.

Swift and Efficient Synthesis of 4-Phenylquinazolines: Involvement of N-Heterocyclic Carbene in the Key Cyclization Step

An original route to 2-alkyamino-4-phenylquinazolines in three steps from simple (hetero)aromatic amines is reported here. The key step involves the intramolecular cyclization of benzoyl arylguanidines performed in [OMIm]Cl ionic liquid. The basic (hetero)aromatic guanidines deprotonate the imidazolium-based ionic liquid, thus triggering the cascade process ultimately leading to the intramolecular cyclization. This reaction is the first example of a Friedel-Crafts-type reaction in which an N-heterocyclic carbene is involved in the formation of the electrophilic intermediate.

Bis(1,3,4-Thiadiazolo)-1,3,5-triaziniumHalides: Access to Highly Substituted Aromatic Guanidines

The reaction of bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides with primary aromatic amines in CHCl3/Et3N yields new highly substituted aromatic guanidines (up to 90% yield).

Chelate Complexes with the P=O Double Bond – a New Concept for Molecular Recognition

Compounds capable of forming chelate complexes with their P=O double bond systems represent excellent host molecules for most of the biologically important classes of organic cations in polar media. Additional cooperative hydrogen bonds render even simple bisphosphonates highly selective: mono- and disaccharides, 1,2- and 1,3-amino alcohols, arginine derivatives in peptidic environment and aromatic guanidines can now be recognized with high efficiency and high selectivity. The Review Article presents this relatively new concept for molecular recognition which imitates in many cases the recognition motifs found in nature itself

Interaction of nonylguanidine with the sodium channel

Alkyl and aromatic guanidines interact strongly with the tetrodotoxin (TTX)- receptor site in eel electroplaque membranes, showing competition with TTX. That these guanidines could be useful as highly reversible small molecular weight blockers of Na+ currents is therefore suggested. We have investigated the mechanisms of interaction of one of these derivatives, nonylguanidine, by studying its effects on Na+ currents in squid giant axons using voltage clamp techniques. Although nonylguanidine competed with TTX for binding to eel electroplaque membrane fragments (Ki = 1.8 X 10(-5) M), it reversibly blocked both inward and outward Na+ currents in intact axons only if applied to the interior. In axons with the Na+ inactivation removed by papain nonylguanidine produced a time-dependent block very similar to that reported for strychnine and pancuronium. The reduction of steady-state currents in these axons was also voltage-dependent, with increasing block observed with increasing step depolarization. These results suggest that nonylguanidine binds to a site accessible from the axoplasmic side of the channel, simulating Na+ inactivation in papain-treated axons and competing with the normal inactivation process in untreated axons. The competition between internal nonylguanidine and external TTX may result from perturbation by the positively charged nonylguanidine of the TTX-binding site from within the channel itself.

Cardiovascular activity of aromatic guanidine compounds.

A series of aromatic guanidines and several 1-phenylbiguanides was prepared and tested for cardiovascular (CV) effects in anesthetized dogs measuring heart rate, blood pressure, carotid artery blood flow, and myocardial force changes. The predominant CV effect at minimally effective dose was vasoconstriction unassociated with cardiac stimulation. The structure-activity relationships of the compounds were discussed comparing their structural similarities to the beta-phenylethylamines. The most potent members of the series were phenylguanidines substituted in the 3 and 4 positions on the aromatic nucleus with hydroxy or chloro groups. Preliminary mechanism studies indicated that the 3,4-dihydroxyphenylguanidines act at least partially by a direct alpha-adrenergic mechanism

ChemInform Abstract: INHIBITION OF PHENYLALANYL‐TRNA SYNTHETASE BY AROMATIC GUANIDINES AND AMIDINES

Chemischer InformationsdienstVolume 6, Issue 35 Preparative Organic Chemistry ChemInform Abstract: INHIBITION OF PHENYLALANYL-TRNA SYNTHETASE BY AROMATIC GUANIDINES AND AMIDINES P. V. DANENBERG, P. V. DANENBERGSearch for more papers by this authorD. V. SANTI, D. V. SANTISearch for more papers by this author P. V. DANENBERG, P. V. DANENBERGSearch for more papers by this authorD. V. SANTI, D. V. SANTISearch for more papers by this author First published: September 2, 1975 https://doi.org/10.1002/chin.197535131Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume6, Issue35September 2, 1975 RelatedInformation

Inhibition of phenylalanyl-tRNA synthetase by aromatic guanidines and amidines.

Aromatic guanidines and amidines were investigated for their ability to inhibit phenylalanyl-tRNA synthetase from E. coli B. 2-Phenylacetamidine (1), benzylguanidine (2), and N-benzylbenzamidine (3) are competive inhibitors with respect to phenylalanine, binding nearly as well as the substrate, The remainder of the inhibitors was unexpectedly found to be noncompetitive, indication the presence of a secondary binding site on the enzyme. Inhibition by these compounds appears to be specific for phenylalanyl-tRNA synthetase and requires the presence of a phenyl ring as well as the amidine or guanidine moiety.