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1.
Eur J Med Chem ; 215: 113275, 2021 Apr 05.
Article in English | MEDLINE | ID: mdl-33618157

ABSTRACT

Combretastatin A-4 inspired heterocyclic derivatives were synthesized and evaluated for their biological activities on tubulin polymerization and cell proliferation. Among the 19 described sulfur-containing compounds, derivatives (Z)-4h and (Z)-4j exhibited interesting in cellulo tubulin polymerization inhibition and antiproliferative activities with IC50 values for six different cell lines between 8 and 27 nM. Furthermore, in silico docking studies within the colchicine/CA-4 binding site of tubulin were carried out to understand the interactions of our products with the protein target. The effects on the cell cycle of follicular lymphoma cells were also investigated at 1-10 nM concentrations showing that apoptotic processes occurred.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Thiophenes/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cattle , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Protein Binding , Stilbenes/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/metabolism , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacology
2.
Bioorg Med Chem Lett ; 26(1): 174-80, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26602281

ABSTRACT

Combretastatin A-4 and isocombretastatin A-4 derivatives having thiophenes or benzo[b]thiophenes instead of the B ring were prepared and evaluated for their in cellulo tubulin polymerization inhibition (TPI) and antiproliferative activities. The presence of the benzo[b]thiophene ring proved to have a crucial effect as most of the thiophene derivatives, except those having one methoxy group, were inactive to inhibit tubulin polymerization into microtubules. The influence of the attachment position was also studied: benzo[b]thiophenes having iso or cis 3,4,5-trimethoxystyrenes at position 2 were 12-30-fold more active than the 3-regioisomers for the TPI activity. Some of the novel designed compounds exhibited interesting anti-proliferative effects on two different cell lines.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Stilbenes/pharmacology , Thiophenes/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , HeLa Cells , Humans , Molecular Docking Simulation , Molecular Structure , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Tubulin/metabolism
3.
J Med Chem ; 58(4): 1832-45, 2015 Feb 26.
Article in English | MEDLINE | ID: mdl-25634041

ABSTRACT

A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/ß-pregnane-3,20-dione or 5ß-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/ß-pregnane-3,20-dione, among which the 5ß-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 µM versus 1.2 and 10.6 µM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5ß-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 µM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Leukemia, Erythroblastic, Acute/drug therapy , Leukemia, Erythroblastic, Acute/metabolism , Progesterone/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cell Survival/drug effects , Crystallography, X-Ray , Humans , K562 Cells , Leukemia, Erythroblastic, Acute/pathology , Models, Molecular , Molecular Conformation , Progesterone/chemical synthesis , Progesterone/chemistry , Tumor Cells, Cultured
4.
Bioorg Med Chem Lett ; 22(23): 7227-31, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23063401

ABSTRACT

A novel series of combretastatin A-4 heterocyclic analogues was prepared by replacement of the B ring with indole, benzofurane or benzothiophene, attached at the C2 position. These compounds were evaluated for their abilities to inhibit tubulin assembly: derivative cis3b, having a benzothiophene, showed an activity similar to those of colchicine or deoxypodophyllotoxine. The antiproliferative and antimitotic properties of cis3b against keratinocyte cancer cell lines were also evaluated and the intracellular organization of microtubules in the cells after treatment with both stereoisomers of 3b was also determined, using confocal microscopy.


Subject(s)
Antimitotic Agents/chemical synthesis , Heterocyclic Compounds/chemistry , Stilbenes/chemistry , Antimitotic Agents/chemistry , Antimitotic Agents/toxicity , Benzofurans/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/pharmacology , Humans , Indoles/chemistry , Microscopy, Confocal , Microtubules/chemistry , Microtubules/metabolism , Stereoisomerism , Stilbenes/chemical synthesis , Stilbenes/toxicity , Thiophenes/chemistry
5.
Steroids ; 77(12): 1177-91, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22868178

ABSTRACT

Bivalent ligands were designed on the basis of the described close proximity of the ATP-site and the putative steroid-binding site of P-glycoprotein (ABCB1). The syntheses of 19 progesterone-adenine hybrids are described. Their abilities to inhibit P-glycoprotein-mediated daunorubicin efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein were evaluated versus progesterone. The hybrid with a hexamethylene linker chain showed the best inhibitory potency. The efficiency of these progesterone-adenine hybrids depends on two main factors: (i) the nature of the linker and (ii) its attachment point on the steroid skeleton.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adenine/chemistry , Drug Design , Drug Resistance, Multiple/drug effects , Progesterone/chemistry , Progesterone/pharmacology , Cell Line, Tumor , Chemistry Techniques, Synthetic , Daunorubicin/pharmacology , Humans , Progesterone/chemical synthesis
6.
Org Biomol Chem ; 6(8): 1364-76, 2008 Apr 21.
Article in English | MEDLINE | ID: mdl-18385843

ABSTRACT

A regioselective synthesis of 4,7-dimethoxy 5- and 6-azaindoles 2 has been achieved, based on the appropriate choice of ortho-directing or ortho-repulsing groups in the formylation of a pyridine ring. Studies on the regioselectivity of the formylation step and on the preparation of azidoacrylate intermediates 4 are described in this paper. The reactivity of the 5- and 6-azaindole structures towards BBr3-mediated selective monodemethylation and oxidative demethylation reactions were also investigated. The regioselectivity of the deprotection was confirmed using a chemical approach. Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile-water, trioxopyrrolopyridines 12 were obtained, whereas the formation of functionalised azaindoles 17 was observed in acetonitrile-methanol. The tautomeric structure of the trioxopyrrolopyridines was proved by X-ray diffraction analysis.


Subject(s)
Aza Compounds/chemistry , Indoles/chemistry , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , Aza Compounds/chemical synthesis , Crystallography, X-Ray , Indoles/chemical synthesis , Models, Molecular , Molecular Structure , Oxidation-Reduction , Pyridines/chemistry , Pyrroles/chemistry , Solvents/chemistry , Stereoisomerism
7.
Org Lett ; 8(18): 3919-22, 2006 Aug 31.
Article in English | MEDLINE | ID: mdl-16928038

ABSTRACT

The reaction between p-quinone monoimide 1a and various azadienes 2 is described in the absence of a Lewis acid promoter. When alpha,beta-unsaturated hydrazones are substituted by proton or alkyl groups, 2,3-dihydrobenzofuranes 4, a motif that is present in numerous biologically active products, are obtained in moderate to excellent yields. The regio- and stereoselectivity of this reaction has been proved by a complete NMR study, including 1H-15N correlations.

8.
Mycoses ; 49(3): 169-75, 2006 May.
Article in English | MEDLINE | ID: mdl-16681806

ABSTRACT

2-Benzenesulphinyl-(1,4)-naphtoquinone and 14 derivatives were synthesised and were used to evaluate their cytotoxicity against a human myelomonocyte cell line and their antifungal activity against two yeast, i.e. Candida albicans and C. tropicalis and against two filamentous fungi such as Aspergillus niger and Fusarium oxysporum and against one dermatophyte, namely Trichophyton tonsurans. The cytotoxicity and antifungal activities were investigated in comparison with amphotericin B as reference drug. No compound was significantly more toxic than amphotericin B at 0.2 microg ml(-1). The best results of antifungal activity were obtained with GFL 10, GFL 13 and GFL 30 on C. tropicalis, F. oxysporum and T. tonsurans. For C. albicans and A. niger, there was no difference between amphotericin B and the other molecules. The sterol quantitation, the time-kill curves were carried out for these three compounds in order to confirm their action in ergosterol synthesis. Time-kill curves showed a fungistatic activity. For C. tropicalis GFL 10, GFL 13 and GFL 30 increased the growth delay better than amphotericin B, in contrast to F. oxysporum. As for T. tonsurans, GFL10 and GFL13 gave a delay, but the effect of GFL 30 was a bit less marked.


Subject(s)
Antifungal Agents/pharmacology , Disulfides/chemical synthesis , Disulfides/pharmacology , Fungi/drug effects , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Amphotericin B/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/toxicity , Cell Line , Disulfides/chemistry , Fungi/classification , Humans , Microbial Sensitivity Tests , Monocytes , Naphthoquinones/chemistry
9.
Eur J Med Chem ; 41(6): 773-8, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16563569

ABSTRACT

3-Arylamino-2-phenylsulfinylnaphthoquinones, 2,3-diarylthio-naphthoquinones and 2-phenylsulfinyl-3-arylthio-1,4-dihydronaphtalenes are synthesized and tested against five fungi. The activities of these products were better than amphotericine B against all the strains except for Candida albicans.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/drug effects , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Drug Evaluation, Preclinical , Microbial Sensitivity Tests , Species Specificity
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