ABSTRACT
Deacetylcolchicine was reacted with substituted benzyl halides to provide a library of compounds for biological analysis. Compound 7 (3,4-difluorobenzyl-N-aminocolchicine) was shown to possess cytotoxicity in cancer cell lines in the low nanomolar range. Significantly, it showed no loss of activity in the resistant A2780AD ovarian carcinoma cell line known to overexpress the ABCB1 drug transporter and was also unaffected by overexpression of class III ß-tubulin in HeLa transfected cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Colchicine/analogs & derivatives , Colchicine/chemical synthesis , Tubulin Modulators/chemical synthesis , ATP-Binding Cassette Transporters/biosynthesis , Antineoplastic Agents/pharmacology , Binding Sites , Cell Cycle/drug effects , Cell Line, Tumor , Colchicine/chemistry , Colchicine/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Microtubules/drug effects , Microtubules/ultrastructure , Models, Molecular , Structure-Activity Relationship , Transfection , Tubulin/chemistry , Tubulin/genetics , Tubulin/metabolism , Tubulin Modulators/pharmacologyABSTRACT
Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III ß-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Colchicine/pharmacology , Prodrugs/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/chemical synthesis , Colchicine/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Structure-Activity RelationshipABSTRACT
A phthalocyanine-chalcone conjugate has been designed to combine the vascular disrupting effect of chalcones with the photodynamic effect of phthalocyanines. This potential dual photodynamic and antiangiogenic agent was obtained by the condensation of a tetrahydroxylated non-peripherally substituted Zn(ii) phthalocyanine with an amino chalcone converted into the corresponding activated isocyanate. The conjugate was fully characterized.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Drug Design , Indoles/chemistry , Organometallic Compounds/chemistry , Photosensitizing Agents/chemical synthesis , Angiogenesis Inhibitors/chemistry , Chalcone/analogs & derivatives , Chalcone/chemistry , Isoindoles , Molecular Structure , Photosensitizing Agents/chemistry , Stereoisomerism , Zinc CompoundsABSTRACT
A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.
Subject(s)
Aniline Compounds/chemistry , Microtubules/chemistry , Stilbenes/chemistry , Triazoles/chemistry , Tubulin Modulators/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Binding Sites , Cell Line, Tumor , Computer Simulation , Humans , Microtubules/metabolism , Protein Structure, Tertiary , Stilbenes/chemical synthesis , Stilbenes/toxicity , Triazoles/chemical synthesis , Triazoles/toxicity , Tubulin Modulators/chemical synthesis , Tubulin Modulators/toxicityABSTRACT
The synthesis based on palladium catalytic coupling of 38 new-arylated benzo[b]thiophenes or thiophenes is described in a few steps. We also report the direct arylation of the position 3 of the benzo[b]thiophenic structure, a 'one pot' 2,5-heterodiarylation of thiophenes as well as the synthesis of precursors of amino-acids with a 2-arylated benzo[b]thiophene core. These compounds were evaluated on bacteria strains: most of them did not exhibit any antibiotic activity but were found to selectively inhibit the NorA multidrug transporter of Staphylococcus aureus. As such, they restored the activity of the NorA substrates ciprofloxacin against a resistant S. aureus strain in which this efflux pump is over-expressed.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Staphylococcus aureus/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Ciprofloxacin/metabolism , Drug Resistance, Multiple, Bacterial/genetics , Drug Screening Assays, Antitumor , Ethidium , Humans , Indicators and Reagents , Macrolides/pharmacology , Microbial Sensitivity Tests , Quinolones/pharmacology , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
Some (1,3')-bis-tetrahydroisoquinolines were reported as scaffold intermediates for the synthesis of pentacyclic piperazine core alkaloids and their cytotoxicity against cancerous cell lines was evaluated. The NMR and X-ray structural assignments revealed an anti C3-C11 backbone stereochemistry of piperazine structures. Inhibition of cancer cell proliferation of (1,3')-bis-tetrahydroisoquinoline scaffolds and pentacyclic piperazine systems was assessed against three human cancer cell lines (K562 myelogenous leukemia, A549 lung carcinoma, MCF-7 breast adenocarcinoma) and both mouse tumor cell lines of blood (P388) and lymphocytic (L1210) leukemia with considerable activity against the latter. The cell cycle analysis was also studied by flow cytometry measurement on K562 cell line.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Chemistry, Pharmaceutical/methods , Neoplasms/drug therapy , Piperazines/chemical synthesis , Piperazines/pharmacology , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Drug Screening Assays, Antitumor , Humans , K562 Cells , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular ConformationABSTRACT
[reaction: see text] Benzo[b]thiophene derivatives are important in part because of their use as selective estrogen receptor modulators. They are usually synthesized by intramolecular cyclization. Here, we propose a method for the synthesis of 2-arylbenzo[b]thiophenes with heteroatoms at the 3-positions directly from the benzo[b]thiophene core by using an aromatic nucleophilic substitution reaction and Heck-type coupling. This methodology provides 2-aryl-3-amino or phenoxybenzo[b]thiophenes in about 35% overall yield in 5 steps.
