L-dopa Derivatives Research Articles

Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics

Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PAN endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PAN inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PAN endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PAN endonuclease activity with an IC50 value of 0.15 μM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PAN endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.

L-DOPA BIOSYNTHESIS WITH Agaricus bisporus TYROSINASES ASSISTANCE

L-DOPA (3,4-dihydroxyphenyl-L-alanine) is a drug of choice in Parkinson's disease treatment. However the chemical method of its synthesis has a number of drawbacks, so biotechnological approaches are being explored as an alternative. Aim. The goal is to develop a new affordable and effective method of biosynthesis of L-DOPA using mushroom tyrosinase, immobilized using an economical carrier, which ensures stability and enzyme multiple uses. Methods. Agaricus bisporus isolated tyrosinase was used in the work. L-DOPA biosynthesis was carried out in aqueous and organic medium. The obtained product was analyzed using mass spectrometry, specific rotation and melting point. The enzyme immobilization was carried out in poly-N-vinylpyrrolidone (PVP), the interaction with the carrier, pH-optimum and the application frequency were determined. Results. A partially purified preparation of tyrosinase was isolated from Agaricus bisporus. In aqueous solution in enzyme presence, only 5.1% of L-DOPA was obtained due to the subsequent formation of complex polycyclic compounds. The biosynthesis of L-DOPA derivative in methylene chloride with the addition of a buffer solution made it possible to obtain a product with a yield of 55%. Tyrosinase immobilized in PVP showed activity 30% higher than free in CH2Cl2 medium and carried out biocatalysis for 7 cycles. Conclusions. A method of L-DOPA synthesizing using an available biocatalyst based on immobilized tyrosinase was developed, which enabled to obtain L-DOPA during 7 cycles of use in a methylene chloride medium.

Radical scavenging abilities of L-tyrosine and L-DOPA Schiff bases and their fluorescence binding studies and molecular docking interactions with bovine serum albumin

Phenolic compounds are known for their abilities to scavenge and eliminate reactive oxygen species (ROS) which may lead to oxidative stress. Bearing in mind that Schiff bases are biologically active compounds, a series of Schiff bases derived from the monophenolic l-tyrosine and diphenolic l-DOPA were synthesized and characterized by spectral and elemental analysis. The structure of the l-DOPA naphthyl Schiff base was confirmed and characterized by X-ray. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical assays were used in assessing the effectiveness of these compounds as radical scavengers. l-DOPA derivatives were better radical scavengers with lower IC50 compared to l-tyrosine derivatives. To understand the distribution of these compounds in the blood plasma, their interactions with bovine serum albumin (BSA) were monitored using fluorescent emission spectroscopy where they were found to quench the BSA intrinsic fluorescence by combined static and dynamic mechanism. The fluorescence and FT-IR data showed that conformational changes occurred in BSA after interaction with the Schiff bases. The binding constant of tyrosine and DOPA Schiff bases were in the order of 104 to 108 M−1 suggesting a moderate to good binding ability with BSA. Higher binding affinity and better radical scavenging ability was observed for compounds bearing the naphthyl moiety.The radical scavenging ability of the l-DOPA naphthyl Schiff base was found to increase with decrease in IC50 values from 17 to 15 µM when bound to BSA. Fluorescence measurement and molecular docking studies demonstrated that hydrophobic interactions and hydrogen bonds dominated the interaction between BSA and tyrosine or l-DOPA derivatives. These results gave valuable information for pharmacological mechanism for l-tyrosine and l-DOPA Schiff bases in vivo conditions which can have a vital role in the development of drugs.

Preparation and intestinal absorption of L-Dopa-D-phenylglycine

L-Dopa-D-phenylglycine was synthesized in this laboratory as L-dopa derivative for improving its intestinal absorption. As designed for transport through the intestine via oligopeptide transporter (PepT1), the competition of this dipeptide with known substrates for PepT1 in brush-border membrane vesicle (BBMV) was investigated. At the presence of L-Glycinyl-L-proline (L-Gly-L-Pro), L-Glycinyl-L-phenylalanine (L-Gly-L-Phe) or cephradine, the uptake of L-dopa-D-phenylglycine in BBMV was reduced to 54.1 ± 4.5%, 57.6 ± 5.2% or 62.9 ± 10.2%, respectively. The inhibition by these dipeptides and the tripeptide mimetic amino-β-lactam was significantly higher than by amino acids L-Phenylalanine (L-Phe) or L-dopa. The results suggested that the intestinal H +-coupled PepT1 was involved in the uptake of L-dopa-D-phenylglycine. The steady state plasma concentrations of L-dopa-D-phenylglycine and L-dopa in rats after a single pass in-situ jejunal perfusion with 0.1 mM perfusate were 104.0 ± 12.90 μg/mL and 1.24 μg/mL respectively. L-Dopa-D-phenylglycine demonstrated a 50.1 fold higher plasma concentration, in terms of molar ratio, than that of L-dopa. D-Phenylglycine was proved to be a satisfactory moiety for the improvement of L-dopa absorption in the intestine.

Anti-biofouling activity of Ranaspumin-2 bio-surfactant immobilized on catechol-functional PMMA thin layers prepared by atmospheric plasma deposition.

The deposition of polymeric thin layers bearing reactive functional groups is a promising solution to provide functionality on otherwise inert surfaces, for instance, for bioconjugation purposes. Atmospheric pressure plasma (AP plasma) deposition technology offers many advantages, such as fast deposition rates, low costs, low waste generation and suitability for coating various kind of material surfaces. In this work, the AP plasma-assisted copolymerization of methyl methacrylate (MMA) with a vinyl derivative of L-DOPA was studied in order to deposit coatings with reactive catechol/quinone groups suitable for protein covalent immobilization. The effect of adding a chemical cross-linker, between 0 and 2 mol%, to the monomer mixture is also studied in order to prepare robust plasma PMMA-based layers in liquid physiological media. The layer prepared with 0.2 mol% of cross-linker shows the best balance between stability in saline-buffered media and surface functionalization. Bioconjugation via the grafting of Ranaspumin-2 recombinant, a naturally occurring surfactant protein, is carried out in a single step after plasma deposition. Protein immobilization is corroborated by Quartz Crystal Microbalance with Dissipation (QCM-D) and Surface Plasmon Resonance (SPR) analyses and confirmed via Epicocconone staining, X-Ray Photoemission Spectroscopy (XPS) and Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS) measurements and surface wettability characterizations. The bio-functionalized layers presented an enhanced activity against the adhesion of Human Serum Albumin (HSA), indicating the grafting potential of the Ranaspumin-2 bio-surfactant to produce anti-biofouling functional coatings.

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64–70μM) for the MDA-MB-231 cell line after 24–48h of treatment, but they were more selective and much more potent (IC50 4–16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1–2μM), probably as the result of slow hydrolysis of their methyl ester functions.

Therapeutic Effect of Hydrogen Sulfide-Releasing L-Dopa Derivative ACS84 on 6-OHDA-Induced Parkinson’s Disease Rat Model

Parkinson’s disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson’s disease.

A Novel Hydrogen Sulfide-releasing N-Methyl-d-Aspartate Receptor Antagonist Prevents Ischemic Neuronal Death

Physiological levels of H(2)S exert neuroprotective effects, whereas high concentrations of H(2)S may cause neurotoxicity in part via activation of NMDAR. To characterize the neuroprotective effects of combination of exogenous H(2)S and NMDAR antagonism, we synthesized a novel H(2)S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H(2)S donor 4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na(2)S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na(2)S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H(2)S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury.

Novel codrugs with GABAergic activity for dopamine delivery in the brain

This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period. These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy.

Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet–Spengler approach

A protocol for the diastereoselective synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via Pictet–Spengler condensation with L-DOPA or l-DOPA derivatives and 1H-indole-3-carbaldehydes is presented. The protocol is used for the successful synthesis of several tetrahydroisoquinolines as well as diketopiperazine fused analogues.

Effects of Hydrogen Sulfide-releasing l-DOPA Derivatives on Glial Activation: POTENTIAL FOR TREATING PARKINSON DISEASE

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (L-DOPA) is the most widely used therapy, but it does not arrest disease progression. Some possible contributing factors to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. Here we demonstrate the properties of four such L-DOPA hybrids based on coupling L-DOPA to four different hydrogen sulfide-donating compounds. The donors themselves were shown to be capable of conversion by isolated mitochondria to H(2)S or equivalent SH(-) ions. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. When human microglia, astrocytes, and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H(2)S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-alpha, interleukin-6, and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. The H(2)S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties.

Electrochemical, Photoelectrochemical, and Piezoelectric Analysis of Tyrosinase Activity by Functionalized Nanoparticles

The electrochemical and photoelectrochemical detection of tyrosinase (TR) activity (an indicative marker for melanoma cancer cells) is reported, using Pt nanoparticles (NPs) or CdS NPs as electrocatalytic labels or photoelectrochemical reporter units. The Pt NPs or CdS NPs are modified with a tyrosine methyl ester, (1), capping layer. Oxidation of the capping layer by TR/O2 yields the respective L-DOPA and dopaquinone products. The reduction of the resulting mixture of products with citric acid yields the L-DOPA derivative,(3), as a single product. The association of the (3)-functionalized Pt NPs or CdS NPs to a boronic acid monolayer-modified electrode enables the electrochemical transduction of TR activity by the Pt-NPs-electrocatalyzed reduction of H2O2 or the photoelectrochemical transduction of TR activity by the generation of photocurrents in the presence of triethanolamine as a sacrificial electron donor. The detection limits for analyzing TR corresponds to 1 U and 0.1 U by the electrochemical and photoelectrochemical methods, respectively. The association of the Pt NPs or CdS NPs to the functionalized monolayer electrode is followed by quartz crystal microbalance measurements.

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines: towards pentacyclic analogues of piperazine core alkaloids

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet–Spengler cyclization and intramolecular peptide coupling. The direct Pictet–Spengler reaction between a derivative of l-DOPA and N-protected-α-aminoaldehyde was first extended to the synthesis of cis-(1,3′)-bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-α-aminoaldehyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3–C11 backbone stereochemistry, were obtained from cyclization para- and ortho- to the 3-OH group of the l-DOPA derivative.

Preparation of Selectively Protected L‐Dopa Derivatives: Oxidation of Tyrosine‐3‐boronates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tert-Butyl (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3′,4′-dimethoxyphenyl)propionate chloroform sesquisolvate

The title compound, C30H33NO6·1.5CHCl3, a derivative of l-DOPA, forms chains in its crystal structure, via weak N—H⋯O=C hydrogen bonds involving the carbamate N—H and carbonyl groups of adjacent mol­ecules, supported by N—H⋯O=C interactions of the same carbonyl. The staggered conformation about the C—C bond joining the di­methoxy­phenyl group to the chiral centre is similar to that in l-DOPA, but different from that in the iodo derivative from which the title compound was prepared. Extensive disorder of the chloro­form solvent mol­ecules, which could not be modelled by discrete atomic sites, prevents the confirmation of the absolute configuration of the main mol­ecule on the basis of anomalous scattering effects of chlorine atoms, demonstrating a limitation of this otherwise useful technique.

Preparation of Selectively Protected L-Dopa Derivatives: Oxidation of Tyrosine-3-boronates

Conversion of 3-iodo-L-tyrosine to protected tyrosine-3-boronate esters, followed by oxidation with hydrogen peroxide, provides a mild and efficient method for the preparation of selectively protected L-dopa derivatives.

Elevation of Plasma Levels of L-Dopa in Transdermal Administration of L-Dopa-Butylester in Rats

ABSTRACTTo increase delivery of L-dopa in its transdermal absorption, a new lipophilic derivative of L-dopa, L-dopa-butylester, was synthesized. An in-vitro study employing two-chamber diffusion cells, in which the excised rat abdominal skin was mounted, revealed that, in the presence of L-menthol and ethanol, L-dopa-butylester penetrated in its original form more effectively than L-dopa. L-Dopa-butylester sheets were made by immersing wiper sheets in methanol containing the compound, and then evaporating the methanol. An extraction study of the compound from the sheets revealed that its stability was maintained for at least 12 weeks. In an in-vivo cutaneous absorption study, an L-dopa-butylester sheet was attached to the shaved rat abdominal skin. A hydrogel containing L-menthol and ethanol was spread on vinyl tape, and this sheet was placed over it. In plasma, the L-dopa level rose linearly between 30 and 180 min after the cutaneous application; L-dopa-butylester was not detected. The L-dopa level was higher than that in which L-dopa was applied. These findings indicated that the lipophilic nature of L-dopa-butylester further increased its penetration through the skin, and that L-dopa-butylester that was taken up into the general circulation system was rapidly converted to L-dopa by hydrolysis in the body.

Dimeric l-Dopa Derivatives as Potential Prodrugs

A series of dimeric derivatives (+)- 1, and (+)- 2, and (+)- 3a–d of l-Dopa diacetyl esters was synthesized and evaluated as potential l-Dopa prodrugs with improved physicochemical properties. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of l-Dopa in human plasma was observed.

A CONVENIENT PREPARATION OF SELECTIVELY PROTECTED L-DOPA DERIVATIVES FROM 3-IODO-L-TYROSINE

Palladium-catalyzed hydroformylation of 3-iodo-L-tyrosine derivatives la,b followed by protection of the free phenol as its benzyl ether and Baeyer-Villiger oxidation of the 3-formyl group provided the desired L-Dopa derivatives 4b,c in 71 and 68% overall yields, respectively.

ChemInform Abstract: An Improved Synthesis of Selectively Protected L‐Dopa Derivatives from L‐Tyrosine.

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