Biomedical subjects

Maria Koufaki

Publications and source records attributed to Maria Koufaki.

9 recordsLinked to original sources

PubMed2006

3D-Quantitative structure-activity relationships of synthetic antileishmanial ring-substituted ether phospholipids.

The application of 2D-NMR spectroscopy and Molecular Modeling in determining the active conformation of flexible molecules in 3D-QSAR was demonstrated in the present study. In particular, a series of 33 flexible synthetic phospholipids, either 2-(4-alkylidene-cyclohexyloxy)ethyl- or omega-cycloalkylidene-substituted ether phospholipids were systematically evaluated for their in vitro antileishmanial activity against the promastigote forms of Leishmania infantum and Leishmania donovani by CoMFA and CoMSIA 3D-QSAR studies. Steric and hydrophobic properties of the phospholipids under study appear to govern their antileishmanial activity against both strains, while the electrostatic properties have no significant contribution. The acknowledgment of these important properties of the pharmacophore will aid in the rational design of new analogues with higher activity.

Animals↗

PubMed2006

Synthesis and biological evaluation of benzopyran analogues bearing class III antiarrhythmic pharmacophores.

We have synthesized a series of compounds combining the hydroxy-benzopyran ring of vitamin E with the methylsulfonylaminophenyl group of class III antiarrhythmic drugs, connected through tertiary amine moieties. Evaluation of the antiarrhythmic and antioxidant activity of the new compounds was carried out on isolated rat heart preparations using the non-recirculating Langendorff mode. The new analogues were present, at 10 microM concentration, during ischemia and reperfusion. Selected compounds were further studied by a conventional microelectrode method in order to get insight into their cellular mode of action. The most active compound, N-[4-[2-[[2-(3,4-dihydro-6-hydroxy-2,2,7,8-tetramethyl-2H-1-benzopyran-5-yl)ethyl] methylamine]ethyl]phenyl]methanesulfonamide (19a), reduces premature beats, prolongs QT and QRS intervals during ischemia and reperfusion, and reduces MDA content, leading to a fast recovery of the heart. In addition, it exhibits moderate class III antiarrhythmic action.

Action Potentials↗

PubMed2006

Chroman/catechol hybrids: synthesis and evaluation of their activity against oxidative stress induced cellular damage.

Three series of chromans substituted at positions 2 or 5 by catechol derivatives were synthesized, and their activity against oxidative stress induced cellular damage was studied. Specifically, the ability of the new molecules to protect cultured cells from H(2)O(2)-induced DNA damage was evaluated using single cell gel electrophoresis (comet assay), while the neuroprotective activity of the new compounds against oxidative stress induced programmed cell death was studied using glutamate-challanged hippocampal HT22 cells. The majority of the new compounds are stronger neuroprotectants than quercetin. 5-Substituted chroman analogues such as the caffeic acid amides 12 and 16 and the dihydrostilbene analogue 24 were the most potent against both H(2)O(2)- and glutamate-induced damage in Jurkat T cells and HT22 cells, respectively.

Antioxidants↗

PubMed2005

Structure-activity relationships of antineoplastic ring-substituted ether phospholipid derivatives.

PURPOSE: Previous studies have shown that alkylphosphocholines (APCs) exhibit strong antineoplastic activity against various tumour cell lines in vitro and in several animal models. The current study was designed to investigate the influence of cycloalkane rings on the antiproliferative activity of APCs against a panel of eight human and animal cell lines (PC3, MCF7, A431, Hela, PC12, U937, K562, CHO). Specifically, we explored the effect of the presence of 4-alkylidenecyclohexyl and cycloalkylidene groups in alkoxyethyl and alkoxyphosphodiester ether lipids, respectively. In addition, the haemolytic activity of the new ring-substituted ether phospholipids (EP) was evaluated. METHODS: Cells were exposed to various concentrations of the compounds for 72 h. The cytotoxicity was determined with the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction assay. Similarly, red blood cells were distributed in 96-well microplates and treated with the test compounds at concentrations ranging from 100 to 6.25 microM for 1 h. After centrifugation, the absorbance of the supernatants was measured at 550 nm. RESULTS: The majority of the compounds tested exhibited significant cytotoxic activity which depended on both the ring size and position with respect to the phosphate moiety, as well as the head group. Among the cycloalkylidene series the 11-adamantylideneundecyl-substituted N-methylmorpholino EP 13 was the most potent and exhibited broad-spectrum anticancer activity comparable to or superior to that of hexadecylphosphocholine (HePC). All the adamantylidene-substituted EPs were nonhaemolytic (concentration that exhibits 50% haemolytic activity, HC(50), >100 microM). Furthermore, the cyclohexylidene-substituted analogues were more potent against the cell lines tested, with the exception of U937 and K562, than the cyclodecapentylidene-substituted compounds. Hydrogenation of the double bond in the cycloalkylidene-substituted EPs (compounds 14 and 15) resulted in improvement of anticancer activity. Among the 2-(4-alkylidenecyclohexyloxy)ethyl EPs, 2-(4-hexadylidenecyclohexyloxy)ethyl phosphocholine (22) possessed the highest broad-spectrum cytotoxic activity than all the other analogues of this series and was nonhaemolytic (HC(50) >100 microM). In general, the 2-(4-alkylidenecyclohexyloxy)ethyl-substituted EPs were more active against the more resistant cell lines U937, K562 and CHO than HePC. CONCLUSIONS: The presence of cycloalkane rings in the lipid portion of APCs reduces haemolytic effects compared to HePC and in several analogues results in improved antineoplastic activity.

Animals↗

PubMed2004

Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmias.

Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogues in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidation. Moreover, the new molecules, at 1 microM concentration, reduced reperfusion arrhythmias and MDA content on isolated rat heart preparations, with the 2- and 5-subtituted chromans possessing the better cardioprotective activity.

Animals↗

PubMed2003

Bifunctional agents for reperfusion arrhythmias: novel hybrid vitamin E/class I antiarrhythmics.

We have synthesized a series of hybrid compounds combining the pharmacophoric redox moieties of vitamin E and key features responsible for the antiarrhythmic properties of the class I antiarrhythmics procainamide and lidocaine. Procainamide analogue (2a) and lidocaine analogues (14a) and (14b) are very strong inhibitors of lipid peroxidation. All analogues tested at 100 or 30 microM enhanced the post ischemic recovery without inducing ventricular fibrillations while there was no evidence in our experiments for drug-induced pro-arrhythmia. In addition, they induced a widening of the QRS intervals. Our data suggest that the efficacy of the new compounds in preventing reperfusion arrhythmias could be attributed to their combined effects involving inhibition of free radical mediated damage coupled with antiarrhythmic properties.

Anti-Arrhythmia Agents↗

PubMed2003

Antileishmanial ring-substituted ether phospholipids.

Three series of ring-substituted ether phospholipids were synthesized carrying N,N,N-trimethylammonium, N-methylpiperidino, or N-methylmorpholino headgroups. The first series is substituted by 2-cyclohexyloxyethyl or 2-(4-alkylidenecyclohexyloxy)ethyl groups, the second series by cyclohexylidenealkyl or adamantylidenealkyl moieties, and the third series by 2-aryloxyethyl or 6-aryloxyhexyl groups in the alkyl portion of the molecule. The antileishmanial activity of the new compounds was evaluated in vitro against the promastigote forms of L. donovani and L. infantum using an MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide)-based microassay as a marker of cell viability. Analogues 12, 15, 24, 30, 32, 41, 43, and 45 were more potent than the control compound miltefosine (hexadecylphosphocholine) against both L. donovani and L. infantum while, derivatives 13 and 42 were equipotent to miltefosine. Analogues 16, 17, 19, 20 were more potent than miltefosine against L. infantumand compounds 27, 31, 44 were more active than miltefosine against L. donovani. Differential scanning calorimetry (DSC) was used to probe the role of individual ether phospholipids on the physicochemical properties of model membranes. The DSC scans showed that the active compounds have a more profound effect on the thermotropic properties of model membrane bilayers than the less active ones.

Animals↗

PubMed2003

Strategies in the design of prodrugs of anti-HIV agents.

Control of AIDS requires development of special therapeutic strategies in order to reduce the level of monocyte/macrophage HIV infection, to prevent spread of HIV within the monocyte/macrophage reservoir, to maintain a therapeutically effective drug concentration in sanctuaries such as the brain and to overcome the problem of cellular resistance mechanisms. A popular approach towards this end has been the development of prodrugs of anti-HIV drugs. This review covers the different strategies devised for the design of prodrugs of anti-HIV agents with emphasis on the recent findings in this field of research. Thus, prodrugs of nucleoside reverse transcriptase inhibitors (NRTIs) including, 5'-O carboxylic ester derivatives, 5'-O- monophosphate analogues, macromolecular derivatives, prodrugs of purine nucleosides, prodrugs of acyclic nucleosides, homo and hetero dinucleotides, prodrugs of non-classical nucleoside analogues, boranophosphate triesters of NRTIs, and prodrugs of protease inhibitors including acyl-substituted prodrugs, prodrugs with increased water solubility, monophosphate prodrugs, and conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers, constitute the subject of this review.

Anti-HIV Agents↗

PubMed2002

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]phenoxyacetic acid.

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.

Acetates↗