A new ring-forming methodology for the synthesis of bioactive pyrroloquinoline derivatives

A new, efficient, two-step method for the synthesis of bioactive pyrroloquinolines is described. Readily available nitroquinolines, bearing the nitro moiety in the carbocyclic ring, are treated with 4-chlorophenoxyacetonitrile in the presence of potassium tert-butoxide/THF to give the analogous vicarious nucleophilic substitution products (5, 8 and 11). These, in turn, are subjected to catalytic hydrogenation to produce 1H-pyrrolo[2,3-f]quinoline (6), 3H-pyrrolo[3,2-f]quinoline (9) and 1H-pyrrolo[3,2-h]quinoline (12) in good yields and relatively short reaction times. The differential activity of two N-alkylated 1H-pyrrolo[2,3-f]quinolines (1) in cisplatin resistant cell lines compared to the corresponding parent lines suggests that these might be useful leads for developing agents for use in drug resistant diseases

Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen

Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen. N-Acetyl-4-S-cysteaminylphenol 1 is an analogue of a biosynthetic intermediate in the pathway to melanin. It is probably oxidized to an o-quinone which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. It is reported to have useful anti-melanoma activity. We previously synthesized a range of analogues of 1 by varying the acyl portion of the amide. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. Thirteen new analogues of 1 containing two methyl groups at the cf.-position of the amino component and various acyl groups have now been prepared and assessed for anti-melanoma activity against six human melanoma cell lines. Most of the new compounds displayed greater cytotoxicity than the lead compound 1. The highest cytotoxicity against the cell lines was observed for the cyclohexylacetamide 11 followed by the cyclohexylcarboxamide 10 and the 2,2-dimethylpropanamide 6. The IC50 values of the most cytotoxic compound 11 against the cell lines were comparable with those of cisplatin. Small variations in the acyl components of these analogues, such as reducing the ring size, lengthening the carbon chain and reducing the amount of chain branching, resulted in a considerable loss of cytotoxicity. The moderate activity of 6, 10 and 11 against SK- Mel-24 cells (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be their only mode of action

Novel imidazothioxanthones: Synthesis, DNA binding and cytotoxicity

A new class of DNA-binding ligands (10a-f) has been synthesized and examined for DNA-binding affinity using thermal denaturation and for in vitro cytotoxicity in a number of cell lines. All the compounds were found to possess significant DNA-binding affinity which correlates with in vitro cytotoxicity across eight cell lines

Antitumor activity of imidazothioxanthones in murine and human tumor models in vitro and in vivo

Background: A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels of human and murine tumor cell lines in vitro, and the in vivo activity against human and murine solid tumors of the most potent compound, N-[3-(Dimethylamino)propylo]-11-oxo-11H-benzothiopyrano [3'2': 2, 3]pyrido[1,2-a] imidazo-2-carboxamide (10a). In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. Materials and Methods: The cytotoxicity of compounds 10a; 11-oxo-N-[2-(pyrrolidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a] imidazo-2-carbaramide, 11-oxo-N-[2-(piperidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a] imidazo-2-carboxamide and N-[2-(morpholino)ethylo]-11-oxo-11H-benzothiopyrano [3'2': 2, 3]pyrido[1,2-a]imidazo-2-carboxamide (10c-10e) was assessed in human tumor cell lines and xenografts using the sulforhodamine B assay, MTT assay and the clonogenic assay. The human ovarian xenograft, PXN/109TC, two human breast carcinomas, MT-1 and MCF-7, and the murine colon adenocarcinoma, MAC 15A were used for the in vivo testing of compound 10a. In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. Results: Two compounds, 10a and 10c, showed cytotoxic activity below 10 mM in the NCI in vitro screen of 60 human tumor cell lines. The IC50 value of compound 10a was 6.8 mM and that of 10c, 8.3 mM. In addition, both compounds possessed differential activity against leukemia, colon and mammary cancer. The activity pattern was confirmed in two further screens using monolayer and clonogenic assays. In vivo antitumor studies showed that 10a was active against the human mammary carcinoma MT-1 and murine colon cancer MAC15A. Marginal activity was observed in human ovarian cancer model PXN/109T/C and the compound was inactive in human mammary cancer MCF-7. Conclusion: The results warrant further in vivo testing of 10a in additional human solid tumor models. The molecular modeling showed that the planarity of the chromophore and the side-chain conformation could assist the insertion of compound 10a between the base pairs of the double helix On the other hand, docking to the nucleotide sequence GGAATTGCCTCA suggested that the molecule could also act as a minor groove binder

Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET

Experience with imaging of the multi-drug resistance (MDR) phenotype in rumours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are required. One approach to these problems is the development of short half-lift positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purification steps. The chemistry is suitable fur use with very short half-lift: radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to support clinical imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is significantly reduced after several months of conditioning in the presence of doxorubicin, which induces increased Pgp expression. Uptake in hooded rat sarcoma (HSN) cells, which express Pgp, is significantly increased in the presence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumour-bearing rats showed uptake in tumour increasing up to 30 min p.i. while it was decreasing in other tissues. for development of radiopharmaceuticals containing copper radionuclides, and that this series of complexes should undergo further evaluation in vivo as position emission tomography imaging agents fur MDR

Performance of Waterborne Polyurethanes in Inhibition of Gas Hydrate Formation and Corrosion: Influence of Hydrophobic Fragments

The design of new dual-function inhibitors simultaneously preventing hydrate formation and corrosion is a relevant issue for the oil and gas industry. The structure-property relationship for a promising class of hybrid inhibitors based on waterborne polyurethanes (WPU) was studied in this work. Variation of diethanolamines differing in the size and branching of N-substituents (methyl, n-butyl, and tert-butyl), as well as the amount of these groups, allowed the structure of polymer molecules to be preset during their synthesis. To assess the hydrate and corrosion inhibition efficiency of developed reagents pressurized rocking cells, electrochemistry and weight-loss techniques were used. A distinct effect of these variables altering the hydrophobicity of obtained compounds on their target properties was revealed. Polymers with increased content of diethanolamine fragments with n- or tert-butyl as N-substituent (WPU-6 and WPU-7, respectively) worked as dual-function inhibitors, showing nearly the same efficiency as commercial ones at low concentration (0.25 wt%), with the branched one (tert-butyl; WPU-7) turning out to be more effective as a corrosion inhibitor. Commercial kinetic hydrate inhibitor Luvicap 55 W and corrosion inhibitor Armohib CI-28 were taken as reference samples. Preliminary study reveals that WPU-6 and WPU-7 polyurethanes as well as Luvicap 55 W are all poorly biodegradable compounds; BODt/CODcr (ratio of Biochemical oxygen demand and Chemical oxygen demand) value is 0.234 and 0.294 for WPU-6 and WPU-7, respectively, compared to 0.251 for commercial kinetic hydrate inhibitor Luvicap 55 W. Since the obtained polyurethanes have a bifunctional effect and operate at low enough concentrations, their employment is expected to reduce both operating costs and environmental impact