N-Heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold with anticancer and anti-infective dual action.

BACKGROUND: Pharmacological effects of biologically active "small molecules" can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom. METHODS: Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT-1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated. RESULTS: Target compounds exhibit high selective cytotoxicity (LC50<1µg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5-32µg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities. CONCLUSIONS: Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics.

1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) increases Carmofur stability and in vitro antiproliferative effect.

Addition of DMPC considerably inhibits the degradation of Carmofur in neutral phosphate buffer solutions and this drug becomes less influenced by pH. Carmofur stabilization at neutral pH caused by DMPC addition for in vitro studies was characterized and monitored by 1H NMR. Antiproliferative activity studies on various tumor cell lines showed considerable increase of Carmofur ability to prevent tumor cell growth, when it is added as a mixture with DMPC. This technique opens a way for Carmofur drug delivery in neutral and basic media.

5-membered cyclic hydroxamic acids as HDAC inhibitors.

The new histone deacylases inhibitors (HDACi) were synthesized in the class of 5-membered cyclic hydroxamic acids (5-CHA), showing medium size CHA as a new Zn-binding group. New reaction sequence was proposed for the synthesis of 5-membered alkylidene-cyclic-hydroxamic acids starting from butyrolactone. Compound 10c showed low µM activity on HeLa cell extracts. From these results, cyclic hydroxamic acids will be further investigated to find more potent compounds.

Thieno[2,3-b]pyridines--a new class of multidrug resistance (MDR) modulators.

To identify new potent multidrug resistance modulators, we have synthesized a series of novel thieno[2,3-b]pyridines and furo[2,3-b]pyridines, and examined their structure-activity relationships. All synthesized compounds were tested to determine BCRP1, P-gp, and MRP1 inhibitor activity, and most potent MDR modulators were also screened for their toxicity, cytotoxicity and Ca(2+) channel antagonist activity. Among these compounds, thieno[2,3-b]pyridine (6r) was found to exhibit a potent P-gp inhibitory action with EC50 = 0.3 ± 0.2 µM, MRP1 inhibitory action with EC50 = 1.1 ± 0.1 µM and BCRP1 inhibitory action with EC50 = 0.2 ± 0.05 µM and may represent suitable candidate for further pharmacological studies.

Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer.

Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.

Synthesis and cytotoxic activity of 1-{3-[1-(5-organylsilylfuran-2-yl)silinan-1-yl]propyl}amines and some trimethylgermyl analogues.

New highly cytotoxic 1-{3-[1-(5-organylsilyl-furan-2-yl)silinan-1-yl]propyl}amines and some trimethylgermyl analogues (IC50 1-7 µg mL(-1)) have been synthesized by a hydrosilylation reaction of aliphatic and heterocyclic N-allylamines in the presence of Speier's catalyst. The effects of the silacycle, the element-organic substituent in position 5 of the furan ring, and the structure of the amine on the cytotoxicity of the new compounds have been studied.

Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3-(benzo)thiazol-2-yl]-ω-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides.

A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)-yl]ethan/propanamide derivatives was synthesized and characterized by (1)H, (13)C NMR and IR spectroscopy and mass-spectrometry. A single crystal X-ray study of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide is reported to determine its conformational feature. The investigated compounds were found to be active in psychotropic in vivo, anti-inflammatory in vivo and cytotoxicity in vitro screening. They possess marked sedative action, reveal high anti-inflammatory activity, have selective cytotoxic effects and NO-induction ability concerning tumour cell lines. Some of the compounds synthesized demonstrate antimicrobial action. An attempt was made to correlate the biological results with their structural characteristics and physicochemical parameters. Some specific combinations of types of activities for the synthesized compounds have been revealed.

Synthesis, structure and cytotoxicity of 3-C, N, S, Se substituted benzo[b]selenophene derivatives.

Synthesis, molecular structure and cytotoxic activity of a series of 3-C, N, S, Se substituted benzo[b]selenophene derivatives on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines are described. The correlation between compound LD(50) 3T3 fibroblast cell line and HT-1080 morphology was shown.

Sulfur containing acyclovir derivatives: synthesis, cytotoxic activity, and cell phenotype studies.

New 2-amino-6-oxo-8-thioxo-9-substituted purine derivatives were prepared and assayed for the in vitro cytotoxic activity. Some products exhibited moderate activity on HT-1080 cells and rather high activity on MG-22A cells.

4-Methyl-1,2,3-selenadiazole-5-carboxylic acid amides: antitumor action and cytotoxic effect correlation.

Synthesis and cytotoxic activity of a series of 4-methyl-1,2,3-selenadiazole-5-carboxylic acid amides on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines are described. The correlation between compound LD(50) and 3T3 fibroblast cell line morphology was shown. In vivo evaluation of amides on mouse sarcoma S-180 confirms high antitumor activity (58-85%).

Doxorubicin prodrug on the basis of tert-butyl cephalosporanate sulfones.

Doxorubicin-cephalosporin prodrug adapted to the development of elastases for the liberation of parent drug was synthesized on the basis of cephalosporanate sulfone esters.

Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones.

6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.

Design of beta-lactams with mechanism based nonantibacterial activities.

The majority of nonantibacterial activities discovered for beta-lactam derivatives during the last 15 years are based on their ability to form a stable covalent complex with nucleophile in the active site of enzymes regulating fundamental physiological processes in mammalian organism such as serine and cysteine proteases, LDL phospholipase A(2), A-independent transacylase and some still indeciphered enzymes. Regulation of their catalytic activity both in vitro and in vivo by compounds designed on the cephalosporin, penicillin and 2-azetidinone base was successfully exploited in the treatment of inflammatory, respiratory, cardiovascular disorders, cancer and other pathologic processes. Availability of X-ray crystallographic data for target enzymes and computational molecular modelling in combination with wide possibilities of structural modifications for commercial natural and synthetic beta-lactams and the chiral blocks allow to consider this class of organic compounds as a perspective source of mechanism based nonantibacterial drugs.

Organoammonium hydroselenites: antitumor action through radical balance regulation.

Organoammonium hydroselenites were synthesized and investigated as potential selective, anticancer prodrugs. These compounds were studied in vitro on human fibrosarcoma (HT-1080), hamster kidney endothelial (BHK 21) and normal mouse embryonic fibroblasts (NIH 3T3). Most of them were very active against HT-1080 (0.6-5.3 g/ml). Amino acid hydroselenites readily increased the nitric oxide (NO) concentration in the culture medium of HT-1080 cells (up to TG(100)=1500%); however, 4-amidohydroximinomethylpyridinium hydroselenite (TG(100)=24%) and o-phenanthrolinium hydroselenite (TG(100)=50%) were free radical inhibitors. All compounds were glutathione peroxidase inhibitors; some of them could also prevent hydrogen peroxide degradation by inhibition of catalase. The influence of the investigated ammonium hydroselenites on tumor cell (HT-1080) morphology was examined. The substances studied were also active in vivo against sarcoma S-180. The role of organoammonium hydroselenites as free radical regulators and their therapeutic antitumor are discussed.

Synthesis and cytotoxicity of silicon and germanium containing pyridine oxime O-ethers.

Silicon and germanium containing pyridine aldoxime, ketoxime and amidoxime O-ethers have been prepared using phase transfer catalytic systems oxime alkyl halide solid KOH 18-crown-6 benzene and oxime alkyl halide solid K(2)CO(3) or Cs(2)CO(3) 18-crown-6 toluene. Cytotoxic activity of silicon and germanium containing pyridine oxime O-ethers was tested in vitro on two monolayer tumor cell lines: MG- 22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). O-[3-Yriethylsilylpropyl]- and O-[3-(1-methyl- 1-silacyclopentyl)propyl] oximes of pyridine aldehydes and ketones exhibit high cytotoxicity. Presence of methyl group in the pyridine ring considerably decreased activity of amidoxime O-ethers. Oxime ethers containing two elements are essentially inactive. For 2-acetylpyridine oxime ethers the activity increases in order of alkyl substituents: Et(3)GeCH(2)CH(2)SiMe(2)CH(2) < Et(3)SiCH(2)CH(2)CH(2) < (CH(2))(4)SiCH(2)CH(2)CH(2). Cytotoxicity of ketoxime O-ethers is considerably lower in comparison with aldoxime O-ethers.

Synthesis and cytotoxicity of silicon containing pyridine and quinoline sulfides.

Silicon containing pyridine and quinoline sulfides have been prepared using phase transfer catalytic system thiol/alkyl halide / solid KOH/18-crown-6 / toluene. The target S-ethers were isolated in yields up to 81%. The cytotoxicity of the synthesized compounds was studied. Among pyridine sulfides S-[3-(1-methyl- 1-silacyclohexyl)propyl] derivatives 5e and 6e exhibit the highest cytotoxicity. Aliphatic silicon derivatives were considerably less active. 8-[(Trimethylsilylmethyl)thio]quinoline (8a) exhibits the highest activity among quinoline sulfides.