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ABSTRACT: Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.
Bioorganic & medicinal chemistry 11/2012; · 2.82 Impact Factor
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ABSTRACT: Malonic acid diamides with two long hydrophobic alkyl chains and a basic polar head group as a new class of non-viral gene transferring compounds have shown high transfection efficiency and moderate toxicity. Based on the results obtained with saturated and unsaturated alkyl residues new derivatives with a more complex head group structure have been synthesized. For this purpose, cationic respectively basic groups were introduced by one or two lysine residues bound via tris(aminoethyl)amine spacer to the malonic acid diamide backbone. By studying in vitro gene delivery an increase of transfection efficacy was observed when using lipids with at least one unsaturated alkyl chain. This leads to cationic lipids exhibiting comparable or even higher transfection efficacies compared to the commercially available transfection agents LipofectAmine™ and SuperFect™. Phase transitions and phase structures of selected compounds have been analyzed and discussed in terms of transfection abilities. Particle size and zeta potential of liposomes and lipoplexes were also determined.
International journal of pharmaceutics 02/2011; 409(1-2):46-56. · 2.96 Impact Factor
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ABSTRACT: P-Glycoprotein (P-gp) plays a central role in the development of resistance against cytostatics in anticancer therapy and against human immunodeficiency virus (HIV) therapeutics of the HIV-1 protease inhibitor type. An approach to reverse the so-called multidrug resistance (MDR) phenomenon by the use of P-gp inhibiting agents is a challenge in the therapy of cancer and AIDS. Effective in-vitro inhibitors have P-gp substrate properties so that the expected in-vivo effects have been disappointing so far. Consequent higher dosages cause toxic effects.
Novel HIV-1 protease inhibitors (H17, JW41, JW33 and JW46) have been evaluated in comparison with ritonavir as P-gp inhibiting agents, in the exclusively P-gp overexpressing model cell line mouse T lymphoma using flow cytometry. The cytotoxic properties against various cell lines were characterized in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay to estimate potential toxic effects in therapeutically relevant concentrations in metabolically active HepG2 cells, drug-sensitive Jurkat cells and in gastric carcinoma cells.
Concentration-dependent effective reversal properties have been discussed in context and proved to be mainly influenced by the number of potential hydrogen bond acceptor functions. The compounds showed no cytotoxic properties in P-gp inhibiting concentration ranges. Ritonavir, a known P-gp substrate, proved to be less toxic in the P-gp expressing cell line than in the nonexpressing cell line at the cell-exposed concentrations and thus showed P-gp substrate properties. Two compounds, H17 and JW41, showed no P-gp substrate properties, with higher toxicity in the P-gp expressing cell line compared with the nonexpressing cell line.
The novel compounds have been shown to be prospective AIDS therapeutics, acting as effective and nontoxic P-gp inhibitors compared with ritonavir, which is a known P-gp inhibitor with unfavourable toxic and P-gp substrate properties.
The Journal of pharmacy and pharmacology. 12/2010; 62(12):1704-10.
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ABSTRACT: Gene delivery using nonviral approaches has been extensively studied as a basic tool for intracellular gene transfer. Despite intensive research activity, the aim of creating a vector which meets all necessary demands has still not been reached. One possibility to solve the nonviral vector associated problem of low transfection efficacy is the development of new cationic amphiphiles. Therefore, the non-glycerol-based cationic lipids 1-9 have been synthesized and tested for in vitro gene delivery experiments. The backbone structure of the lipids consists of a malonic acid diamide with two long hydrophobic chains. The degree of saturation of the hydrophobic chains and the structure of the polar cationic headgroup were varied. The preparation follows an easy process and facilitates the trouble-free insertion of different alkyl chains. By studying in vitro gene delivery an increase of transfection efficacy was observed when using at least one unsaturated alkyl chain in the hydrophobic part and lysine or bis(2-aminoethyl)aminoethylamid as hydrophilic headgroup. This leads to cationic lipids exhibiting comparable or even higher transfection efficacies compared to the commercially available LipofectAmine and SuperFect.
Bioconjugate Chemistry 03/2010; 21(4):696-708. · 4.93 Impact Factor
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ABSTRACT: General syntheses of novel symmetrical, single-chain, diacetylene-modified bolaphospholipids have been carried out in five steps. For the ω-alkynols, which have an important role as key intermediates, three different synthetic approaches were comprehensively investigated. For the final synthesis it is suggested that (1) alkylation of lithium (trimethylsilyl)acetylide with tetrahydropyranyl-protected ω-bromoalcohols, followed by (2) cleavage of the trimethylsilyl moiety and the tetrahydropyranyl protecting group, and (3) copper(II)-catalyzed Eglinton coupling is the best strategy for obtaining diacetylene-modified alkane-1,ω-diols, because higher yields were obtained while avoiding the formation of by-products. Moreover, conversion of the diols into bipolar phospholipids was achieved by bis-phosphorylation with β-bromoethylphosphoric acid dichloride and subsequent quaternization with trimethylamine or dimethylamine. Finally, spectral data are presented for novel single-chain, diacetylene-modified bolaphospholipids with promising potential as starting molecules in the formation of polymerizable and, thus, thermostable nanofibers.
Monatshefte für Chemie 01/2010; 141(3):339-349.
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ABSTRACT: Investigation of DNA interactions with cationic lipids is of particular importance for the fabrication of biosensors and nanodevices. Furthermore, lipid/DNA complexes can be applied for direct delivery of DNA-based biopharmaceuticals to damaged cells as non-viral vectors. To obtain more effective and safer DNA vectors, the new cationic lipids 2-tetradecylhexadecanoic acid-{2-[(2-aminoethyl)amino]ethyl}amide (CI) and 2-tetradecylhexadecanoic acid-2-[bis(2-aminoethyl)amino]ethylamide (CII) were synthesized and characterized. The synthesis, physical-chemical properties and first transfection and toxicity experiments are reported. Special attention was focused on the capability of CI and CII to complex DNA at low and high subphase pH values. Langmuir monolayers at the air/water interface represent a well-defined model system to study the lipid/DNA complexes. Interactions and ordering of DNA under Langmuir monolayers of the new cationic lipids were studied using film balance measurements, grazing incidence X-ray diffraction (GIXD) and X-ray reflectivity (XR). The results obtained demonstrate the ability of these cationic lipids to couple with DNA at low as well as at high pH value. Moreover, the observed DNA structuring seems not to depend on subphase pH conditions. An influence of the chemical structure of the lipid head group on the DNA binding ability was clearly observed. Both compounds show good transfection efficacy and low toxicity in the in vitro experiments indicating that lipids with such structures are promising candidates for successful gene delivery systems.
ChemPhysChem 10/2009; 10(14):2471-9. · 3.41 Impact Factor
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ABSTRACT: Chemotherapy is one of the most important methods in the treatment of cancer. However, development of drug resistance during chemotherapy is the leading cause of treatment failure and decreased survival in cancer patients. Multidrug resistance (MDR) is one of the extensively studied forms of drug resistance for more than 30 years. The members of ATP-binding cassette protein family are responsible for multidrug resistance with P-glycoprotein as most representative transporter. To overcome multidrug resistance, pharmacological modulation of the transporters by efflux pump inhibitors seem to be the first choice, but preclinical studies did not lead to clinical applications. Therefore, a systematical research for pharmacophor structures is a promising strategy to increase the efficacy of those drugs still influencing multidrug resistance. In this study a range of phenothiazine derivatives was synthesizied with systematical variation of three molecule domains. The biochemical determination of multidrug resistance reversal activity was achieved with the crystalviolet assay on LLC-PK1/MDR1 cells. The results will be discussed considering of hypotheses in the literature directed to new structure-acitivity relationships to overcome drug resistance in the future.
Archiv der Pharmazie 10/2008; 341(10):624-38. · 1.71 Impact Factor
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ABSTRACT: Substrate and inhibitor properties of H17 as novel modulator of transmembrane efflux pump activities have been characterized in an in situ absorption model. Poor substrate properties towards P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) have been demonstrated. In competition with a MRP substrate H17 proved to have strong MRP-inhibiting properties. The profile of a strong inhibitor with poor substrate properties makes H17 a perspective hopeful candidate for effective therapies of transmembrane efflux pump activities.
European journal of medicinal chemistry 08/2008; 44(7):3060-3. · 3.27 Impact Factor
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ABSTRACT: Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoprotein (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we synthesized a series of compounds that differ in the aromatic core structure, the linker, and the basic moiety. For our search of new aromatic core structures we synthesized novel 2,2-diphenyl-1,3-dioxolane, 2,2- diphenyl-1,3-dioxane, and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds were tested in vitro using human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells were determined with a MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.
Bioorganic & Medicinal Chemistry 04/2007; 15(6):2283-97. · 2.92 Impact Factor
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ABSTRACT: Cationic liposomes/DNA complexes can be used as nonviral vectors for direct delivery of DNA-based biopharmaceuticals to damaged cells and tissues. In order to obtain more effective and safer liposome-based gene transfection systems, the new cationic lipid 2-amino-3-hexadecyloxy-2-(hexadecyloxymethyl)propan-1-ol (AHHP) was synthesized. In this paper we report on the synthesis of AHHP and investigations of its physical-chemical properties. Langmuir monolayers of AHHP were studied at the air/buffer interface by film balance measurements, grazing incidence X-ray diffraction (GIXD), and infrared reflection absorption spectroscopy (IRRAS). Structure and thermotropic phase behavior of AHHP in aqueous dispersion were examined by small-angle and wide-angle X-ray scattering (SAXS/WAXS) and differential scanning calorimetry (DSC). The results show clear differences in structure and phase behavior of AHHP, both in the monolayer system and in aqueous dispersions, in dependence on the subphase pH due to protonation or deprotonation of the primary amine in the lipid head group. Thermodynamic data derived from pi-A isotherms provide information about the critical temperature (Tc), which is in rough agreement with the temperature of the lipid phase transition from gel to fluid state (Tm) found by X-ray and calorimetry studies of AHHP aqueous dispersions. The packing properties of the molecules in mono- and bilayer systems are very similar. DNA couples to the monolayer of the new lipid at low as well as at high pH but in different amounts. The DNA coupling leads to an alignment of adsorbed DNA strands indicated by the appearance of a Bragg peak. The distance between aligned DNA strands does not change much with increasing monolayer pressure.
Langmuir 04/2007; 23(7):3919-26. · 4.19 Impact Factor
