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Faustino Mollinedo - One of the best experts on this subject based on the ideXlab platform.
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erk1 2 acts as a switch between necrotic and apoptotic cell death in Ether Phospholipid edelfosine treated glioblastoma cells
Pharmacological Research, 2015Co-Authors: Sara Melolima, M C Lopes, Faustino MollinedoAbstract:Glioblastoma is characterized by constitutive apoptosis resistance and survival signaling expression, but paradoxically is a necrosis-prone neoplasm. Incubation of human U118 glioblastoma cells with the antitumor alkylPhospholipid analog edelfosine induced a potent necrotic cell death, whereas apoptosis was scarce. Preincubation of U118 cells with the selective MEK1/2 inhibitor U0126, which inhibits MEK1/2-mediated activation of ERK1/2, led to a switch from necrosis to caspase-dependent apoptosis following edelfosine treatment. Combined treatment of U0126 and edelfosine totally inhibited ERK1/2 phosphorylation, and led to RIPK1 and RelA/NF-κB degradation, togEther with a strong activation of caspase-3 and -8. This apoptotic response was accompanied by the activation of the intrinsic apoptotic pathway with mitochondrial transmembrane potential loss, Bcl-xL degradation and caspase-9 activation. Inhibition of ERK phosphorylation also led to a dramatic increase in edelfosine-induced apoptosis when the alkylPhospholipid analog was used at a low micromolar range, suggesting that ERK phosphorylation acts as a potent regulator of apoptotic cell death in edelfosine-treated U118 cells. These data show that inhibition of MEK1/2-ERK1/2 signaling pathway highly potentiates edelfosine-induced apoptosis in glioblastoma U118 cells and switches the type of edelfosine-induced cell death from necrosis to apoptosis.
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quantitative determination of the antitumor alkyl Ether Phospholipid edelfosine by reversed phase liquid chromatography electrospray mass spectrometry application to cell uptake studies and characterization of drug delivery systems
Journal of Chromatography B, 2004Co-Authors: Maria J Blancoprieto, M A Campanero, Faustino MollinedoAbstract:Abstract Edelfosine is a synthetic alkyl Ether Phospholipid that represents a promising class of antitumor agents. However, analytical methods to measure these type compounds are scarce. The lack of a reliable methodology to quantify edelfosine is a major problem in ongoing and scheduled preclinical and clinical trials with this drug. We evaluated the applicability of high-performance liquid chromatography–mass spectrometry to determine edelfosine in biological samples and polymeric delivery systems. Sample pre-treatment involved polymer precipitation or cell lysis with methanol. HPLC separation was performed on an Alltima RPC 18 narrow-bore column and edelfosine quantification was done by electrospray ionization mass spectrometry (ESI-MS) using positive ion mode and selected ion monitoring. Assays were linear in the tested range of 0.3–10 μg/ml. The limit of quantification was 0.3 ng/sample in both matrices, namely biological samples and polymeric delivery systems. The interassay precision ranging from 0.79 to 1.49%, with relative errors of −6.7 and 12.8%. Mean extraction recovery was 95.6%. HPLC–ESI-MS is a reliable system for edelfosine analysis and quantification in samples from different sources, combining advantages of full automation (rapidity, ease of use, no need of extensive extraction procedures) with high analytical performance and throughput.
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fluorescent phenylpolyene analogues of the Ether Phospholipid edelfosine for the selective labeling of cancer cells
Journal of Medicinal Chemistry, 2004Co-Authors: Ernesto Quesada, Consuelo Gajate, Faustino Mollinedo, Javier Delgado, Ulises A Acuna, F AmatguerriAbstract:Edelfosine (ET-18-OCH3), a synthetic antitumor Ether lipid, is taken up by malignant but not by normal cells, triggering apoptosis in a large variety of human tumor cells. The synthesis of the first fluorescent edelfosine analogue (6), with apoptotic activity comparable to that of the parent drug, is described. Fluorescence microscopy experiments show that 6 selectively labels human cancer cells, accumulating into specific domains of the plasma membrane.
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biological activities mechanisms of action and biomedical prospect of the antitumor Ether Phospholipid et 18 och3 edelfosine a proapoptotic agent in tumor cells
Current Drug Metabolism, 2002Co-Authors: Consuelo Gajate, Faustino MollinedoAbstract:The work of the authors was supported by grant CDTI 97-0355 from INKEYSA and Ministerio de Industria y Energia of Spain, and grants 1FD97-2018-C02-01 and 1FD97-0622 from the European Commission and Comision Interministerial de Ciencia y Tecnologia of Spain.
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Induction of apoptosis in human mitogen-activated peripheral blood T-lymphocytes by the Ether Phospholipid ET-18-OCH3: Involvement of the Fas receptor/ligand system
British Journal of Pharmacology, 1999Co-Authors: Christelle Cabaner, Consuelo Gajate, Antonio Macho, Manuel Modolell, Eduardo Munoz, Faustino MollinedoAbstract:Activated T-cells constitute a target for treatment of autoimmune diseases. We have found that the antitumour Ether Phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3; edelfosine) induced dose- and time-dependent apoptosis in human mitogen-activated peripheral blood T-lymphocytes, but not in resting T-cells. T-lymphocytes were stimulated with phytohemagglutinin and interleukin-2 or with concanavalinA. Apoptosis was assessed by DNA fragmentation through cell cycle and TUNEL analyses, as well as through visualization of internucleosomal DNA fragmentation in agarose gels. The ET-18-OCH3-mediated apoptotic response in activated T-lymphocytes was less intense than in human leukaemic T cell lines, such as Jurkat cells and Peer cells; namely about 25% apoptosis in activated T-cells versus about 4661% apoptosis in T leukaemic cells after 24h treatment with 10μM ET-18-OCH3. The ET-18-OCH3 thioEther analogue BM41.440 (ilmofosine) showed a similar apoptotic capacity to that found with ET-18-OCH3 in activated T-cells, whereas the Phospholipid analogue hexadecylphosphocholine (miltefosine) failed to promote this response. The uptake of 3H-ET-18-OCH3 was much larger in activated T-cells than in resting lymphocytes. Using a cytofluorimetric approach we have found that ET-18-OCH3 induced disruption of the mitochondrial transmembrane potential and production of reactive oxygen species in activated T-cells, but not in resting lymphocytes. ET-18-OCH3 induced an increase in Fas (APO-1/CD95) ligand mRNA expression in activated T-cells, and incubation with a blocking anti-Fas (APO-1/CD95) antibody partially inhibited the ET-18-OCH3-induced apoptosis of activated T-lymphocytes. These results demonstrate that mitogen-activated T-cells, unlike resting lymphocytes, are able to take up significant amounts of ET-18-OCH3, and are susceptible to undergo apoptosis by the Ether lipid via, in part, the Fas (APO-1/CD95) receptor/ligand system. This ET-18-OCH3 apoptotic action can be of importance in the therapeutic action of this Ether lipid in certain autoimmune diseases.
Irene Fragiadaki - One of the best experts on this subject based on the ideXlab platform.
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Design and synthesis of potent antileishmanial cycloalkylidene-substituted Ether Phospholipid derivatives.
Journal of Medicinal Chemistry, 2008Co-Authors: Theodora Calogeropoulou, Panagiotis Angelou, Irene Fragiadaki, Anastasia Detsi, Effie ScoulicaAbstract:Two series of novel Ether Phospholipids (EPs) have been synthesized. The first includes cyclodecylidene- or cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 21 23, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 µM against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fol...
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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 μ M 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 μ M ). 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 μ M ). 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.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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.
Theodora Calogeropoulou - One of the best experts on this subject based on the ideXlab platform.
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Design and synthesis of potent antileishmanial cycloalkylidene-substituted Ether Phospholipid derivatives.
Journal of Medicinal Chemistry, 2008Co-Authors: Theodora Calogeropoulou, Panagiotis Angelou, Irene Fragiadaki, Anastasia Detsi, Effie ScoulicaAbstract:Two series of novel Ether Phospholipids (EPs) have been synthesized. The first includes cyclodecylidene- or cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 21 23, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 µM against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fol...
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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 μ M 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 μ M ). 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 μ M ). 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.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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.
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Ether Phospholipid azt conjugates possessing anti hiv and antitumor cell activity synthesis conformational analysis and study of their thermal effects on membrane bilayers
Journal of Medicinal Chemistry, 2001Co-Authors: Thomas Mavromoustakos, Theodora Calogeropoulou, Maria Koufaki, Antonios Kolocouris, I Daliani, Costas Demetzos, Zhaoxing Meng, Alexandros Makriyannis, Jan Balzarini, Erik De ClercqAbstract:The 1-O-hexadecyl-2-O-methyl-sn-glyceryl phosphodiester AZT 4 and hexadecyl-phosphodiester AZT 5 derivatives were synthesized and found to be active against HIV-1, HIV-2, and tumor cell proliferation. Compared to AZT, compound 4 possessed ca. 10-fold lower anti-HIV activity and ca. 10-fold higher anti-tumor cell activity. Compound 5 was 10-fold less potent than compound 4 in both biological tests. In an attempt to correlate biological activity of compounds 4 and 5 with structure, their conformational and thermal effects on membrane bilayers were compared using a combination of NMR spectroscopy, computational analysis, and Differential Scanning Calorimetry. The obtained results showed that compound 4 adopts a compact conformation in which the alkyl chain, the 2-methoxyglyceryl functionality, and the methyl group of thymine are in spatial proximity, while analogue 5 possesses a less compact conformation of the nucleoside base and the alkyl chain. The presence of the 2-methoxyglyceryl group in compound 4 may...
Maria Koufaki - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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 μ M 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 μ M ). 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 μ M ). 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.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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.
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Ether Phospholipid azt conjugates possessing anti hiv and antitumor cell activity synthesis conformational analysis and study of their thermal effects on membrane bilayers
Journal of Medicinal Chemistry, 2001Co-Authors: Thomas Mavromoustakos, Theodora Calogeropoulou, Maria Koufaki, Antonios Kolocouris, I Daliani, Costas Demetzos, Zhaoxing Meng, Alexandros Makriyannis, Jan Balzarini, Erik De ClercqAbstract:The 1-O-hexadecyl-2-O-methyl-sn-glyceryl phosphodiester AZT 4 and hexadecyl-phosphodiester AZT 5 derivatives were synthesized and found to be active against HIV-1, HIV-2, and tumor cell proliferation. Compared to AZT, compound 4 possessed ca. 10-fold lower anti-HIV activity and ca. 10-fold higher anti-tumor cell activity. Compound 5 was 10-fold less potent than compound 4 in both biological tests. In an attempt to correlate biological activity of compounds 4 and 5 with structure, their conformational and thermal effects on membrane bilayers were compared using a combination of NMR spectroscopy, computational analysis, and Differential Scanning Calorimetry. The obtained results showed that compound 4 adopts a compact conformation in which the alkyl chain, the 2-methoxyglyceryl functionality, and the methyl group of thymine are in spatial proximity, while analogue 5 possesses a less compact conformation of the nucleoside base and the alkyl chain. The presence of the 2-methoxyglyceryl group in compound 4 may...
Panagiota Papazafiri - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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 μ M 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 μ M ). 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 μ M ). 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.
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Structure-activity relationships of antineoplastic ring-substituted Ether Phospholipid derivatives
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Panagiota Papazafiri, Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou, Maria Koufaki, Efi Scoulica, Irene FragiadakiAbstract: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.