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1.
Ceska Slov Farm ; 72(4): 155-164, 2023.
Article in English | MEDLINE | ID: mdl-37805261

ABSTRACT

In continuation of our published review on general inhalational anesthetics, the current article presents a survey of intravenous agents for general anaesthesia. From chemical point of view these compounds belong to structurally diverse categories, such as barbiturates - thiopental (Sodium pentothal®, Trapanal®, Pentothal®), methohexital (Brevital®), and hexobarbital (Evipan®, Hexenal®, Citopan®, Tobinal®); non-barbiturate derivatives - ketamine (Ketalar® Ketaset®), esketamine (Ketanest®), and etomidate (Amidate®, Hypnomidate®), phenolic derivatives - propofol (Diprivan®); steroid derivatives - mixture of alfadolone and alfaxalone (Althesin® in human and Saffan® in veterinary anesthesia); and derivatives of phenylacetic acid - propanidid (Epontol®, Sombrevin®). Most of these compounds are chiral, with the exception of propofol and propanidid. Apart from etomidate and esketamine, they are used in the form of their racemates. Besides their characteristics and mechanism of action, attention is centred also on their chiral properties.


Subject(s)
Alfaxalone Alfadolone Mixture , Etomidate , Propofol , Humans , Thiopental , Etomidate/pharmacology , Propofol/pharmacology , Propanidid , Anesthetics, Intravenous/pharmacology , Methohexital
2.
Life (Basel) ; 13(7)2023 Jul 06.
Article in English | MEDLINE | ID: mdl-37511891

ABSTRACT

A series of Schiff base ligands obtained by the condensation of trans-cyclohexane-1,2-diamine and fluorinated benzaldehydes were prepared, followed by their reduction with NaBH4. The reduced ligands were employed in the synthesis of zinc complexes of the general formula [ZnCl2(L)]. The structures of both the original and the reduced Schiff bases, as well as of the zinc complexes, were characterized by single-crystal X-ray analysis, along with NMR and IR spectroscopy. The antimicrobial activities of the reduced Schiff bases and their zinc complexes were evaluated in vitro against E. coli, S. aureus, and C. albicans. The compounds containing the 4-(trifluoromethylphenyl) moiety showed marked antibacterial activity. Interestingly, the antimicrobial effect of the zinc complex with this moiety was significantly higher than that of the corresponding free reduced ligand, comparable with ciprofloxacin used as standard. Thus, a synergic effect upon the complexation with zinc can be inferred.

3.
Int J Mol Sci ; 24(6)2023 Mar 16.
Article in English | MEDLINE | ID: mdl-36982753

ABSTRACT

Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates-equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.


Subject(s)
Chemistry, Pharmaceutical , Drug-Related Side Effects and Adverse Reactions , Humans , Stereoisomerism
4.
Ceska Slov Farm ; 70(2): 51-58, 2021.
Article in English | MEDLINE | ID: mdl-34237944

ABSTRACT

The present paper reports the synthesis of a series of seven compounds with a hetero aminopropanol chain. The compounds were prepared by the conversion of 3-alkoxy-4-hydroxyphenyl alkanones with 2-chloromethyl oxirane and subsequent reaction of the products with heterocyclic amines (pyrrolidine, azepane, 4-methylpiperazine and 2-methoxyphenyl piperazine). The target compounds were synthesized in the form of racemates. The purity of the products was confirmed by thin layer chromatography and their IR, UV-VIS and 1H-NMR spectra were recorded. Enantioseparation of the racemic products was accomplished by HPLC on a Chiralpak AD chiral chromatographic column with tris(3,5-dimethylphenyl)carbamate as the chiral selector. The efficiency of enantioseparation was determined in relation to the composition of the mobile phase (hexane : ethanol : methanol : ethylethanamine) and to the structure of the prepared compounds. Baseline separation was achieved with all compounds using mobile phases A (78 : 11 : 11 : 0,1 v/v/v/v) and B (80 : 10 : 10 : 0,1 v/v/v/v), with selectivity factor ranging from 1.07 to 1.42 and resolution from 0.76 to 5.47. The mobile phase containing a higher amount of hexane did not allow for successful enantioseparation of the piperazine derivatives.


Subject(s)
Carbamates , Ethanol , Alcohols , Chromatography, High Pressure Liquid , Stereoisomerism
5.
Ceska Slov Farm ; 69(3): 121-129, 2020.
Article in English | MEDLINE | ID: mdl-32972155

ABSTRACT

Bioactive metal complexes represent a promising and rapidly evolving area of pharmacotherapy. After the first part of our survey on metallopharmaceuticals dealing with antimicrobial activity of metal complexes and their application in diagnostics and the second part dedicated to anticancer properties of these compounds, this third and last part of the review focuses on several other applications of metals in therapy (mainly on the therapy of rheumatoid arthritis, some mental diseases, diabetes, as well as on chelation therapy). Following a brief account of the historical development of clinical use of the respective category of drugs, their chemical properties, toxicity, clinical applications and mechanism of action are discussed. The aim of this brief survey is to provide basic outline of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.


Subject(s)
Coordination Complexes/pharmacology , Medicine/trends , Pharmacy/trends , Metals/pharmacology
6.
Molecules ; 25(12)2020 Jun 12.
Article in English | MEDLINE | ID: mdl-32545678

ABSTRACT

Thanks to the progress made in chemical technology (particularly in the methodologies of stereoselective syntheses and analyses) along with regulatory measures, the number of new chiral drugs registered in the form of pure enantiomers has increased over the past decade. In addition, the pharmacological and pharmacokinetic properties of the individual enantiomers of already-introduced racemic drugs are being re-examined. The use of the pure enantiomer of a drug that has been used to date in the form of a racemate is called a "chiral switch". A re-examination of the properties of the pure enantiomers of racemates has taken place for local anesthetics, which represent a group of drugs which have long been used. Differences in (R) and (S)-enantiomers were found in terms of pharmacodynamic and pharmacokinetic activity as well as in toxicity. Levobupivacaine and robivacaine were introduced into practice as pure (S)-(-)-enantiomers, exhibiting more favorable properties than their (R)-(+)-stereoisomers or racemates. This overview focuses on the influence of chirality on the pharmacological and toxicological activity of local anesthetics as well as on individual HPLC and capillary electrophoresis (CE) methods used for enantioseparation and the pharmacokinetic study of individual local anesthetics with a chiral center.


Subject(s)
Anesthetics, Local/chemistry , Stereoisomerism , Chemistry, Pharmaceutical/methods , Levobupivacaine/chemistry
7.
Ceska Slov Farm ; 69(1): 3-16, 2020.
Article in English | MEDLINE | ID: mdl-32460505

ABSTRACT

Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug - cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.


Subject(s)
Antineoplastic Agents/therapeutic use , Coordination Complexes/therapeutic use , Metals/therapeutic use , Neoplasms/drug therapy , Humans
8.
Ceska Slov Farm ; 67(5-6): 182-191, 2018 12 18.
Article in English | MEDLINE | ID: mdl-30871323

ABSTRACT

Metals and their compounds have been exploited in medicine since the dawn of history. All metals (or their substances) exert some kind of biological activity. Metal complexes exhibit a number of unique properties as compared to purely organic substances, stemming from the presence of the metal atom and the variable arrangement of ligands around this central atom. The goal of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public. The first part concentrates on some historical aspects of metallopharmacy and on current application of metals in the therapy of infectious diseases and in diagnostics.


Subject(s)
Coordination Complexes/pharmacology , Pharmacy , Metals
9.
Molecules ; 21(12)2016 Dec 17.
Article in English | MEDLINE | ID: mdl-27999327

ABSTRACT

In order to evaluate the influence of substitution on biological properties of Schiff bases and their metal complexes, a series of differently substituted fluorine-containing Schiff bases starting from the drug isoniazid (isonicotinylhydrazide) were prepared and their structures were established by single-crystal X-ray diffraction. Also, four copper(II) complexes of these Schiff bases were synthesized. The prepared compounds were evaluated for their antimicrobial activity and urease inhibition. Two of the Schiff bases exerted activity against C. albicans. All copper(II) complexes showed excellent inhibitory properties against jack bean urease, considerably better than that of the standard inhibitor acetohydroxamic acid.


Subject(s)
Coordination Complexes/chemistry , Schiff Bases/chemistry , Anti-Infective Agents/pharmacology , Benzaldehydes , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Copper , Crystallography, X-Ray , Escherichia coli , Halogenation , Inhibitory Concentration 50 , Isoniazid , Molecular Structure , Schiff Bases/pharmacology , Structure-Activity Relationship , Urease/antagonists & inhibitors , X-Ray Diffraction
10.
Arch Pharm (Weinheim) ; 349(9): 733-40, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27417385

ABSTRACT

The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential ß-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The ß-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (ß1 ) and trachea (ß2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as ß1 /ß2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7) mol/dm(3) showed also negative chronotropic effects.


Subject(s)
Acebutolol/analogs & derivatives , Acebutolol/pharmacology , Celiprolol/analogs & derivatives , Celiprolol/pharmacology , Propanolamines/chemistry , Propanolamines/pharmacology , Adrenergic beta-Antagonists/chemical synthesis , Adrenergic beta-Antagonists/pharmacology , Animals , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , Histamine/pharmacology , Isoproterenol/pharmacology , Propanolamines/chemical synthesis , Structure-Activity Relationship , Trachea/drug effects
11.
Leg Med (Tokyo) ; 20: 27-31, 2016 May.
Article in English | MEDLINE | ID: mdl-27161918

ABSTRACT

Synthetic cannabinoids as designer drugs constitute a major problem due to their rapid increase in number and the difficulties connected with their identification in complex mixtures. DART (Direct Analysis in Real Time) has emerged as an advantageous tool for the direct and rapid analysis of complex samples by mass spectrometry. Here we report on the identification of six synthetic cannabinoids originating from seized material in various matrices, employing the combination of ambient pressure ion source DART and hybrid ion trap - LTQ ORBITRAP mass spectrometer. This report also describes the sampling techniques for the provided herbal material containing the cannabinoids, either directly as plant parts or as an extract in methanol and their influence on the outcome of the analysis. The high resolution mass spectra supplied by the LTQ ORBITRAP instrument allowed for an unambiguous assignment of target compounds. The utilized instrumental coupling proved to be a convenient way for the identification of synthetic cannabinoids in real-world samples.


Subject(s)
Cannabinoids/isolation & purification , Designer Drugs/isolation & purification , Mass Spectrometry/methods , Chromatography, Gas
12.
J Inorg Biochem ; 147: 147-52, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25920686

ABSTRACT

Four new complexes of group 12 metals [Zn(II), Cd(II) and Hg(II)], along with vanadyl bound to the ligand N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediacetic acid, have been synthesized and characterized. The structure of the complexes with Zn(II), Hg(II) and V(IV) was determined by X-ray structural analysis. In all observed cases, the symmetry of these complexes was found to be distorted octahedral. The inhibition of protein tyrosine phosphatase 1B by the vanadium(IV) complex was demonstrated. The cytotoxicity of the vanadium(IV) complex was tested in vitro against three cancer cell lines, with a comparison of the activity of the free ligand and of vanadyl acetylacetonate and sodium orthovanadate. The IC50 values of the complex were in the range of 9 to 21µM. Remarkably, cytotoxic potency in the multidrug-resistant non-small cell lung cancer cell line A549 was at least as high as in the broadly chemosensitive ovarian teratocarcinoma cell line CH1(PA-1).


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemistry , Coordination Complexes/chemical synthesis , Ethylenediamines/chemistry , Vanadium Compounds/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Ethylenediamines/pharmacology , Humans , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors
13.
Gen Physiol Biophys ; 32(3): 429-41, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23846260

ABSTRACT

We studied the involvement of O2, pH and low molecular thiols in H2S-induced decomposition of S-nitrosoglutathione (GSNO). The GSNO decomposition - •NO release was evaluated by UV-VIS spectroscopy and Griess assay. The H2S donor Na2S was used. O2 slightly increased, but was not necessary for the H2S-induced GSNO decomposition. The rate of GSNO decomposition depended on pH; the maximum rate was observed at pH 7.4-8.0, and this decreased with lowering pH (6.4-4.5) as well as with increasing pH at 9.0-12.0. H2S-induced GSNO decomposition was slowed by the presence of other thiols, such as L-cysteine (Cys), N-acetyl-L-cysteine (NAC) and L-glutathione (GSH), but not in the presence of L-methionine (Met) or oxidized glutathione (GSSG). In sharp contrast, at pH 6.0, H2S-induced GSNO decomposition was negligible, yet the presence of Cys, NAC and GSH induced the H2S-driven GSNO decomposition (whilst Met and GSSG were inactive). In conclusion we postulate an involvement of low molecular thiols and pH in •NO signaling, by modulating the interactions of H2S with nitroso compounds, and hence in part they also appear to control H2S-triggered •NO release. The interaction of H2S and/or its derivatives with the thiol group may be responsible for the observed effects.


Subject(s)
Hydrogen Sulfide/metabolism , Nitric Oxide/metabolism , Oxygen/metabolism , S-Nitrosoglutathione/metabolism , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/metabolism , Hydrogen-Ion Concentration , Molecular Weight
14.
J Med Chem ; 53(20): 7356-64, 2010 10 28.
Article in English | MEDLINE | ID: mdl-20886814

ABSTRACT

Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Leukemia L1210/drug therapy , Leukemia L1210/pathology , Mice , Mice, Inbred DBA , Neoplasm Transplantation , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Oxaliplatin , Stereoisomerism , Structure-Activity Relationship
15.
Eur J Med Chem ; 40(11): 1149-55, 2005 11.
Article in English | MEDLINE | ID: mdl-16040163

ABSTRACT

In order to improve the pharmacological profile of the anticancer drug oxaliplatin, (trans-R,R-cyclohexane-1,2-diamine)oxalatoplatinum(II), and to explore activity-structure relationships, new mono- and dialkyl substituted oxaliplatin analogues have been synthesized. Following a new synthetic strategy, racemates with a defined stereochemistry at carbon atoms 1, 2, 4, and 5 of the cyclohexane ring could be prepared, which are the bases for reliable structure-activity relationships and the following enantiomer resolution. The cytotoxicity was evaluated in nine tumor cell lines, indicating that bulky substituents have a negative influence on the cytotoxic potency of the oxaliplatin derivatives. With respect to the antiproliferative properties, the 4-methyl-, cis-4,5-dimethyl-, and especially the 4,4-dimethyl-trans-cyclohexane-1,2-diamine(oxalato)platinum(II) complexes are the most promising candidates to be further evaluated.


Subject(s)
Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemical synthesis , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Diamines/chemical synthesis , Diamines/chemistry , Drug Screening Assays, Antitumor , Humans , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Oxaliplatin , Structure-Activity Relationship , Tumor Cells, Cultured
16.
Electrophoresis ; 26(4-5): 878-884, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15714548

ABSTRACT

Microemulsion electrokinetic chromatography (MEEKC) was applied for the separation and lipophilicity estimation of oxaliplatin and eight novel anticancer oxaliplatin derivatives. Solubility and permeability have to be balanced in modern drug development, and the octanol-water partition coefficient (log P) still represents one of the most useful quantifiable parameters providing a reasonable estimation of a drug's lipophilicity. Therefore, the capacity factors from MEEKC were correlated to log P values derived by the traditional shake flask method. The MEEKC method was accomplished using a microemulsion of heptane/sodium dodecyl sulfate (SDS)/butanol in phosphate buffer at pH 7.4 and 37 degrees C with all analytes being in a neutral state during the run. This experimental setup allowed a baseline separation of all platinum complexes within 11 min. Remarkably, beside the very good resolution and precision of the measurements, separation of diastereomers of the complexes and quantification of the diastereomeric ratios could be achieved. Correlating the capacity factors with the corresponding log P values resulted in a linear dependency with a correlation factor of r = 0.9935. Consequently, the applied MEEKC method was found to be a highly valuable technique not only for the separation of platinum complexes but as well for the estimation of the octanol-water partition coefficient with many advantages in comparison to other methods.


Subject(s)
Antineoplastic Agents/isolation & purification , Chromatography, Micellar Electrokinetic Capillary/methods , Platinum Compounds/isolation & purification , Electrophoresis, Capillary/methods , Emulsions , Reproducibility of Results
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