Andrzej Stanczak

Determination of the lipophilicity of pyrimido[5,4.c]quinoline derivatives by reversed-phase thin-layer chromatography. Part 1. Lipophilicity of pyrimido[5,4.c]quinolin-4(3H)-ones and 1,2,3,4-tetrahydropyrimido[5,4-c]quinolin-2,4-diones

The lipophilicity of new bioactive pyrimido[5,4-c]quinolin-4(3H)-ones and 1,2,3,4-tetrahydropyrimido[5,4-c]quinolin-2,4-diones has been determined by reversed-phase thin-layer chromatography with DMF-TRIS buffer as mobile phase. The RM values of the compounds were linearly dependent on the concentration of DMF in the mobile phase. Experimental lipophilicity (log PTLC - log D74) was determined by use of a calibration curve prepared by chromatography of six standards. The partition coefficients (log P) were calculated by use of software and compared with experimental values of log PVLC (log D7.4) and log Pneutral for the non-ionized molecules. The dissociation constant (p)Ka) was calculated for all the compounds by use of the pKalc 3.1 prediction module of the Pallas system and used to define the partition coefficient (log Pneutral) of the compounds which can ionize under the experimental conditions. To evaluate the validity of the pKa values obtained, experimental p.Ka values were determined for the quinoline nitrogen atom of the compounds by UV-visible spectroscopic measurements.

Anticancer activity of some polyamine derivatives on human prostate and breast cancer cell lines

The aim of this study was to expand our knowledge about anticancer activity of some polyamine derivatives with quinoline or chromane as terminal moieties. Tested compounds were evaluated in vitro towards metastatic human prostate adenocarcinoma (PC3), human carcinoma (DU145) and mammary gland adenocarcinoma (MCF7) cell lines. Cell viability was estimated on the basis of mitochondrial metabolic activity using water-soluble tetrazolium WST1 to establish effective concentrations of the tested compounds under experimental conditions. Cytotoxic potential of polyamine derivatives was determined by the measurement of lactate dehydrogenase activity released from damaged cells, changes in mitochondrial membrane potential, the cell cycle distribution analysis and apoptosis assay. It was revealed that the tested polyamine derivatives differed markedly in their antiproliferative activity. Bischromane derivative 5a exhibited a rather cytostatic than cytotoxic effect on the tested cells, whereas quinoline derivative 3a caused changes in cell membrane integrity, inhibited cell cycle progression, as well as induced apoptosis of prostate and breast cancer cells which suggest its potential application in cancer therapy.

Application of Chromatographic Data in QSAR Studies of 3-[ω-(4-Arylpiperazin-1-yl)alkyl]pyrimido[5,4-c]quinolin-4(3H)-one Derivatives as 5-HT1A Receptor Ligands

The activity of several 3-[ω-(4-arylpiperazin-1-yl)alkyl]pyrimido[5,4-c]quinolin-4(3H)-ones (LCAPs) with well-defined serotonin 1A (5-HT1A) receptor affinity was described by using chromatographic and calculated physicochemical parameters in quantitative structure-activity relationship analysis. Normal-phase thin-layer chromatography plates impregnated with solutions of L-aspartic acid, L-serine, L-phenylalanine, L-tryptophan, L-tyrosine, L-asparagine, L-threonine and their mixtures (denoted as S1-S11 biochromatographic models) were used with two mobile phases as a model of the interaction between LCAP and 5-HT1A receptors. Molecular descriptors for the investigated compounds were calculated by using HyperChem and ACD/Labs programs. The significant relationship explains that 82% of the variance was successfully validated by leave-one-out and leave-many-out tests. The results demonstrated that this model has significant predictive ability and can be used for the preliminary screening of newly synthesized potential 5-HT1A receptor ligands.

Structure of 1,4-dihydro-1-ethyl-4-iminecinnoline-3-carboxylic acids, classical isosters of quinolone antibacterials: Crystal structures of hydrochlorides of 7-chloro and 7-methyl derivatives

AbstractCrystal structures of hydrochlorides of 7-chloro- and 7-methyl-4-iminecinnoline analogs of antibacterial quinolones have been determined by X-ray diffraction methods. The cell parameters for the 7-chloro (1) analog in the space group P21/c are a = 9.061(1), b = 19.062(1), c = 7.310(1)Å, β = 104.92(1)°, Z = 4, and Dcalc = 1.569 g/cm3 and for the 7-methyl (2) analog in the space group P

Synthesis, Biological Activity and Preliminary in Silico ADMET Screening of Polyamine Conjugates with Bicyclic Systems

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Cinnoline Derivatives with Biological Activity

are a = 7.277(5), b = 9.080(5), c = 10.058(5) Å, α = 106.10(1), β = 102.38(1), γ = 90.18(1)°, Z = 2, and Dcalc = 1.429 g/cm3. Despite geometrical equivalency of methyl and chlorine and some resemblance of their packings, the crystal structures are not isostructural. Each compound forms a strong intramolecular hydrogen bond between protonated 4-imine (a donor) and 3-carboxylic (an acceptor) groups. Compounds with a similar bond, but with reversed functionality and orientation of the 3-carboxylic group, form common quinolones, being mostly 4-oxoquinoline-3-carboxylic acids. The difference should exclude chemical affinity of 4-imine analogs to the guanine base of a bacterial DNA in DNA-gyrase complex, as proposed by Shen et al.2 for 4-oxoquinoline-3-carboxylic acids showing antibacterial activity. Also the free acidic function of a carboxyl group may significantly lower permeability of 4-imine-3-carboxylic analogs of quinolones. Surprisingly, they have demonstrated antibacterial activity comparable with that of nalidixic acid.

Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT1A/2A and 5-HT7 receptor ligands

Assessing hemocompatibility of anticancer drug candidate is a very important task due to the fact that coagulation disorders are often correlated with malignancy or induced by chemotherapy. The aim of this study was to examine the influence of some polyamine conjugates with bicyclic systems on the process of coagulation and fibrinolysis. In addition, their effect on the healthy human erythrocytes (RBCs) was assessed. Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), clot formation and lysis test (CL-test) were performed to evaluate the influence of some polyamine conjugates on plasma hemostasis. The effects of tested compounds on RBCs were assessed using hemolysis assays and microscopy studies. APTT and PT examinations revealed that all tested compounds apart from the highest concentrations of compounds 3 and 5 did not exert significant effects on intrinsic and extrinsic coagulation pathways. Despite their substantial influence on the kinetic parameters of the process of clot formation and fibrinolysis, the examined compounds, over the entire concentration range, did not alter the overall potential of clot formation and lysis (CLAUC) suggesting that they might be regarded as biocompatible concerning plasma hemostasis. At potential therapeutic concentrations (constituting IC50 value for MCF-7 cells) tested polyamine conjugates showed no adverse effects on the membranes of RBCs. The promising antiproliferative activity of representative polyamine conjugates together with their hemocompatibility make them good anticancer drug candidates for further preclinical evaluation.

Synthesis and Biological Evaluation of New Bischromone Derivatives with Antiproliferative Activity

Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC–3, DU–145 and MCF–7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds–DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.