15 research outputs found
Phosphinotripeptidic Inhibitors of Leucylaminopeptidases
Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases.This research was funded by the Polish Ministry of Science and Higher Education (PMSHE) for the Faculty of Chemistry of Wrocław University of Science and Technology and by Wroclaw Research Center EIT+ under the project “Biotechnologies and advanced medical technologies—BioMed”, grant number POIG 01.01.02-02-003/08-00, 00 financed from the European Regional Development Fund (Operational Programme Innovative Economy, 1.1.2. B. O. is recipient of a Ph.D. fellowship from a project funded by the European Social Found. Financial support by the Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) y Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-101818-B-I00, UE), and Gobierno Vasco (GV), (IT 992-16) is gratefully acknowledged
1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties
Schröder DC, Kracker O, Fröhr T, et al. 1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties. Frontiers in Chemistry. 2019;7: 155.Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1H-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1H-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and α-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Ψ[4Tz]Phe-LeuΨ[4Tz]Phe-LeuΨ[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(AlaΨ[4Tz]Ala)6-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)6-OAll and Boc-Ala-(GlyΨ[4Tz]Ala)6-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted “S”-shape, while the Gly variant exhibits no clear secondary structure
Influence of ΔPhe residues on Conformation of peptide chain
In the past few years dehydropeptides have been highly investigated, mainly due to their biological activity: for instance, as antimicrobials or catalytic agents in some enzymes [1, 51-53]. In presented studies it was established that dehydrophenylalanine residue (ΔPhe) can be an interesting building block of various peptide chains, in order to control and modify a structure, conformation and function of the target molecule [3, 4, 5-7]. It was also pointed out that the length of a linker between dehydroamino acid residues (if two or more are present in a peptide chain) is a crucial factor in case of conformational dependence [23]. Short, one-residue spacers promote 310-helical structure, while longer ones increase the coexistence of 310-helical and α-helical conformers (Table 7).
What is worth to notice, temperature or polarity of solvent can dramatically change the screw sense of obtained 310-helices (Table 11). Additionally, the screw sense can be altered by other variables, like chirality of C and N-terminus or dehydroamino acid isomer type (E or Z) [4-11]. Considering chain conformation, it can be disparate, depending on environment’s solid or liquid state (Table 7).
Application of dehydropeptides is widely spread among assorted field of studies. As they can form a few self-assembled structures (e.g. nanotubes, nanovesicles or hydrogels), arise an opportunity of encapsulation of small drug molecules or trapping and releasing bioactive substances [47-49]. Sequences with incorporated dehydroamino acid residues were examined as a potential drug - interaction with negatively charged membrane of bacteria species is possible by virtue of positive polarization of peptide chain [51]. Part of the sequences exert an activity against E. coli, S. aureus, P. falciparum or highly dangerous MRSA, presenting versatile potential correlated with their secondary structure [50-53]
Peptidomimetics and aromatic foldamers in biological chemistry
The interests of the research group working under the supervision of professor Rafał Latajka at the Department of Bioorganic Chemistry at the Wrocław University of Science and Technology are focused on several projects in the field of biological chemistry. Regardless of whether a given project concerns – the synthesis and activity of new enzyme inhibitors, peptides, peptidomimetics, or aromatic foldamers – the thread of correlation between the structure and activity of the studied systems always plays a pivotal role. In this article we are presenting current projects in our research group
Slow Inversion of Stereoisomers of 4-Amino-1-benzylpiperid-4-yl Phosphonic Acids and Their Esters
Coordination Properties of Tris(2-carboxyethyl)phosphine, a Newly Introduced Thiol Reductant, and Its Oxide
Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries
Conformation of dehydropentapeptides containing four achiral amino acid residues – controlling the role of L-valine
Structural studies of pentapeptides containing an achiral block, built from two dehydroamino acid residues (ΔZPhe and ΔAla) and two glycines, as well as one chiral L-Val residue were performed using NMR spectroscopy. The key role of the L-Val residue in the generation of the secondary structure of peptides is discussed. The obtained results suggest that the strongest influence on the conformation of peptides arises from a valine residue inserted at the C-terminal position. The most ordered conformation was found for peptide Boc-Gly-ΔAla-Gly-ΔZPhe-Val-OMe (3), which adopts a right-handed helical conformation
Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries
Location of Varying Hydrophobicity Zinc(II) Phthalocyanine-Type Photosensitizers in Methoxy Poly(ethylene oxide) and Poly(l‑lactide) Block Copolymer Micelles Using <sup>1</sup>H NMR and XPS Techniques
Hydrophobic
zinc(II) phthalocyanine-type derivatives, solubilized
in polymeric micelles (PMs), provide a befitting group of so-called
nanophotosensitizers, suitable for a variety of photodynamic therapy
(PDT) protocols. The factors that influence the success of such products
in PDT are the location of the active cargo in the PMs and the nanocarrier-enhanced
ability to safely interact with biological systems and fulfill their
therapeutic functions. Therefore, the aim of this work was to determine
the solubilization loci of three phthalocyanines of varying hydrophobicity,
i.e., zinc(II) phthalocyanine (ZnPc), along with its tetrasulfonic
acid (ZnPc-sulfo<sub>4</sub>) and perfluorinated (ZnPcF<sub>16</sub>) derivatives, loaded in polymeric micelles of methoxy poly(ethylene
oxide)-<i>b</i>-poly(l-lactide) (mPEG-<i>b</i>-PLLA), by means of <sup>1</sup>H nuclear magnetic resonance (NMR)
and X-ray photoelectron spectroscopy (XPS) combined with ion sputtering.
Furthermore, the microenvironment influence upon the chemical and
physical status of the solubilized cargo in PMs, expressed by photobleaching
and reactive oxygen species (ROS) generation comparing to the same
properties of native cargoes in solution, was also evaluated and discussed
in regards to the probing location data. The studied phthalocyanine-loaded
PMs exhibited good physical stability, high drug-loading efficiency,
and a size of less than ca. 150 nm with low polydispersity indices.
The formation of polymeric micelles and the solubilization locus were
investigated by <sup>1</sup>H NMR and XPS. ZnPc localized within the
PM core, whereas both ZnPcF<sub>16</sub> and ZnPc-sulfo<sub>4</sub> – in the corona of PMs. We proved that the cargo locus is
crucial for the photochemical properties of the studied phthalocyanines;
the increase in photostability and ability to generate ROS in micellar
solution compared to free photosensitizer was most significant for
the photosensitizer in the PM core. Our results indicate the role
of the cargo location in the PM microenvironment and demonstrate that
such attempts are fundamental for improving the properties of photosensitizers
and their assumed efficiency as nanophotosensitizers in PDT