ABSTRACT
A library of functionalized 3-(α-styryl)-benzo[b]thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo[b]thiophene derivatives through a bromocyclization step of methylthio-containing alkynes using N-methylpyrrolidin-2-one hydrotribromide reagent (MPHT). Further coupling of 3-bromobenzothiophenes under palladium-catalysis with N-tosylhydrazones efficiently furnished 2-aryl-3-(α-styryl)benzo[b]thiophene derivatives. The antiproliferative properties of target compounds were studied. Among them, compound 5m has demonstrated submicromolar cytotoxic activity against HCT-116 cell line, and inhibited the polymerization of tubulin at micromolar level comparable to that of CA-4.
Subject(s)
Antineoplastic Agents/chemical synthesis , Styrenes/chemical synthesis , Thiophenes/chemical synthesis , Tubulin/physiology , Alkynes/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Catalysis , Cell Survival/drug effects , HCT116 Cells , Humans , Hydrazones/chemistry , Models, Molecular , Molecular Docking Simulation , Palladium/chemistry , Structure-Activity Relationship , Styrenes/chemistry , Styrenes/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A common dearomative strategy toward the kapakahines B/F and chaetominine natural products is reported. The proposed biomimetic strategy generates the tetracyclic α-carboline core in a single step, featuring a selectfluor-mediated dearomatization of preactivated N-Phth-Trp-Xaa-OR dipeptides at the C-terminus. The pivotal cascade includes a double annulation and the formation of three carbon-heteroatom bonds while gaining, for the first time, some insight on the diastereoselectivity outcome during the formation of the α-carboline fragment.
Subject(s)
Diazonium Compounds/chemistry , Indole Alkaloids/chemical synthesis , Oligopeptides/chemistry , Peptides, Cyclic/chemical synthesis , Tryptophan/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Indole Alkaloids/chemistry , Molecular Conformation , Peptides, Cyclic/chemistry , StereoisomerismABSTRACT
A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)(2) and Cs(2)CO(3) has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give α-branched amines in good yields.
Subject(s)
Amines/chemistry , Copper/chemistry , Hydrazones/chemistry , Amines/chemical synthesis , Catalysis , Oxidation-ReductionABSTRACT
The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G2/M phase cell-cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel-like structures formed by human umbilical vein endothelial cells (HUVECs) inâ vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1-ethane bridge encountered in isoerianin derivatives can replace the 1,2-ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group.
Subject(s)
Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Bibenzyls/therapeutic use , Bibenzyls/toxicity , Binding Sites , Cell Division , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , G2 Phase , Humans , Molecular Conformation , Neoplasms/drug therapy , Phenol , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/therapeutic use , Tubulin Modulators/toxicityABSTRACT
Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.
