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1.
Eur J Med Chem ; 87: 298-305, 2014 Nov 24.
Article in English | MEDLINE | ID: mdl-25262050

ABSTRACT

New benzopsoralen analogues were synthesized and their inhibitory effect on the growth of tumourtumour cell lines (MDA MB231 and TCC-SUP) was evaluated. The in vitro antitumour activity of the new benzopsoralen analogues was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds to evaluate the potential of these molecules to interact with the haem group of the enzymes. The results demonstrated that the compounds that are able to interact with the iron ion of the haem cofactor and at the same time with active site Asn297 are those that have better anti-proliferative activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Ficusin/chemical synthesis , Ficusin/pharmacology , Molecular Docking Simulation , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Coumarins/chemistry , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Ficusin/chemistry , Ficusin/metabolism , Humans
2.
Bioorg Med Chem ; 21(17): 5047-53, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23886808

ABSTRACT

New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.


Subject(s)
Antineoplastic Agents/chemical synthesis , Ficusin/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Aryl Hydrocarbon Hydroxylases/chemistry , Aryl Hydrocarbon Hydroxylases/metabolism , Binding Sites , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Cytochrome P-450 CYP2A6 , Drug Screening Assays, Antitumor , Ficusin/chemical synthesis , Ficusin/toxicity , HeLa Cells , Humans , Molecular Docking Simulation , Structure-Activity Relationship
3.
Food Chem Toxicol ; 58: 95-100, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23607932

ABSTRACT

Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds.


Subject(s)
Anti-Infective Agents/pharmacology , Benzoates/pharmacology , Cinnamates/pharmacology , Glucuronides/chemistry , Melanins/metabolism , Plant Extracts/pharmacology , Reishi/chemistry , Acetylation , Benzoates/chemistry , Cinnamates/chemistry , Esters , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization
4.
Eur J Med Chem ; 43(4): 771-80, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17692432

ABSTRACT

Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC(50) values below 1 microM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors.


Subject(s)
Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Xanthine Oxidase/antagonists & inhibitors , Allopurinol/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured/drug effects , Xanthine Oxidase/metabolism
5.
J Org Chem ; 68(3): 1024-9, 2003 Feb 07.
Article in English | MEDLINE | ID: mdl-12558431

ABSTRACT

Cyclic voltammetry and controlled-potential electrolysis have been employed to investigate and characterize the reductive intramolecular cyclization of ethyl 2-bromo-3-(3',4'-dimethoxyphenyl)-3-(propargyloxy)propanoate (1) promoted by (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane)nickel(I), [Ni(tmc)](+), electrogenerated at glassy carbon cathodes in dimethylformamide containing tetraalkylammonium salts. Cyclic voltammograms for reduction of [Ni(tmc)](2+) in the presence of 1 reveal that [Ni(tmc)](+) catalytically reduces 1 at potentials more positive than those required for direct reduction of 1. During controlled-potential electrolyses of solutions containing [Ni(tmc)](2+) and 1, catalytic reduction of the latter proceeds via one-electron cleavage of the carbon-bromine bond to form a radical intermediate that undergoes cyclization to afford 2-(3',4'-dimethoxyphenyl)-3-(ethoxycarbonyl)-4-methylenetetrahydrofuran (2). In the presence of a base (either electrogenerated or deliberately added as potassium tert-butoxide), 2 rearranges to give 2-(3',4'-dimethoxyphenyl)-3-(ethoxycarbonyl)-4-methyl-2,5-dihydrofuran (3). A mechanistic scheme is proposed to explain the results obtained by means of cyclic voltammetry and controlled-potential electrolysis.

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