ABSTRACT
In order to design and synthesize a new class of heterocyclic analogues of natural combretastatin A-4 and its synthetic derivative AVE8062, the benzoxazolone ring was selected as a scaffold for a bioisosteric replacement of the ring B of both molecules. A library of 28 cis- and trans-styrylbenzoxazolones was obtained by a modified Wittig reaction under Boden's conditions. Structures of the newly synthesized compounds bearing the 3,4,5-trimethoxy-, 3,4-dimethoxy-, 3,5-dimethoxy-, and 4-methoxystyryl fragment at position 4, 5, 6 or 7 of benzoxazolone core were determined on the basis of spectral and X ray data. The in vitro cytotoxicity of styrylbenzoxazolones against different cell lines was examined. Stilbene derivative 16Z, (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzoxazolone, showed highest antiproliferative potential of the series, with IC50 of 0.25 µM against combretastatin resistant cell line HT-29, 0.19 µM against HepG2, 0.28 µM against EA.hy926 and 0.73 µM against K562 cells. Furthermore, the results of flow cytometric analysis confirmed that 16Z induced cell cycle arrest in G2/M phase in the cell lines like combretastatin A-4. This arrest is followed by an abnormal exit of cells from mitosis without cytokinesis into a pseudo G1-like multinucleate state leading to late apoptosis and cell death. Accordingly, synthetic analogue 16Z was identified as the most promising potential anticancer agent in present study, and was selected as lead compound for further detailed investigations.
Subject(s)
Antineoplastic Agents/chemistry , Benzoxazoles/chemistry , Bibenzyls/pharmacology , Small Molecule Libraries/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance/drug effects , Humans , Molecular StructureABSTRACT
Considering that oxidative stress is strongly implicated in the toxicity of chemotherapy, much effort is focused on the research of diverse antioxidants as protective agents. An efficient synthesis of three novel benzophenones containing 1,3-thiazol moiety (6a-c) is described. Their antioxidant power was evaluated in vitro and in three cell lines (the cancerous MCF7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cells). One analogue 5-(2,5-dihydroxybenzoyl)-2(3H)-benzothiazolone (6c), displayed an important antioxidant activity, a low cytotoxicity, and could decrease reactive oxygen species production generated by tert-butyl hydroperoxide (tBHP) in all three cell lines. Interestingly, 6c was able to protect the non-cancerous cells against tBHP-induced death. Further studies are underway to determine its relevance as an adjuvant in oxidative stress inducing chemotherapy.
Subject(s)
Antioxidants/chemical synthesis , Antioxidants/pharmacology , Benzophenones/chemical synthesis , Benzophenones/pharmacology , Antioxidants/chemistry , Benzophenones/chemistry , Cell Death/drug effects , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Molecular Structure , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , StereoisomerismABSTRACT
Various chiral N-palmitoyl amino acid surfactants (AAS) derived from methionine, proline, leucine, threonine, phenylalanine and phenylglycine were prepared and converted to their sodium salt. The properties of the aggregates formed in aqueous solution were studied for both the optically-active compounds and their racemic mixture. Characterization was made by surface tensiometry, fluorimetry, dynamic light scattering, circular dichroism (CD) and transmission electron microscopy. It appeared that most of the AAS studied in this work spontaneously formed different types of aggregates, including micrometer-sized aggregates. No significant difference could be found between the critical aggregation concentration (cac) value of pure enantiomers and that of the racemic forms. CD spectra did not reveal any aggregation-induced chirality.