ABSTRACT
The present work describes the preparation of a novel series of compounds based on the structure of goniothalamin (1), a natural styryl lactone with known cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 17 goniothalamin analogues displaying the 5-methyl-2,5-dihydrofuran-2-one motif were prepared, and their cytotoxicity evaluated. While the analogues bearing methoxy and/or hydroxy groups on the aromatic moiety usually were at least three times less potent than the lead compound (1), ortho and para-trifluoromethyl analogues 10 and 11 exhibited levels of cytotoxicity similar to goniothalamin (1) against most cancer cell lines evaluated. One could suggest that the electronic effect of the trifluoromethyl group activates the inhibitor's electrophilic site via reduction of the electron density of the α,ß-unsaturated ester oxygen atom. These results provide new information on the structure activity relationship of these α,ß-unsaturated styryl lactones, thereby further focusing the design of novel candidates.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , Furans/chemistry , Pyrones/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Furans/toxicity , HT29 Cells , Humans , K562 Cells , MCF-7 Cells , Pyrones/chemical synthesis , Pyrones/toxicity , Structure-Activity RelationshipABSTRACT
In this work the antiproliferative activity of goniothalamin (1), both in racemic and in its enantiomeric pure forms, in a solid tumor experimental model using laboratory animals is described. The antiedematogenic activity displayed by racemic 1 in the carrageenan edema model in mice together with the reduction of Ehrlich solid tumor model suggest a relationship between anticancer and antiinflammatory activities with the antiinflammatory activity favoring the antiproliferative activity itself.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Pyrones/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Carrageenan/toxicity , Cell Line, Tumor , Disease Models, Animal , Edema/chemically induced , Edema/drug therapy , Humans , Mice , Pyrones/chemistry , Pyrones/toxicity , StereoisomerismABSTRACT
A naphthopyranone dimer, named planifolin, was isolated from a methylene chloride extract of the capitula of Paepalanthus planifolius Koern. The molecule (C(31)H(26)O(10)) appeared to be made up of two monomeric portions, semi-vioxanthin and paepalantine (an isocoumarin), linked by an ether bond, and it may possess several kinds of biological activity that can be related to its polyphenolic structure. Short-term tests that detect genetic damage can afford the information needed to evaluate carcinogenic risks of chemicals to humans. The Ames test, recommended for testing the mutagenicity of chemical compounds with potential pharmacological application, was used in the present study. The mutagenic activity was evaluated in Salmonella typhimurium strains TA100, TA98, TA102 and TA97a and the cytotoxic effect in McCoy cells. The in vitro cytotoxicity of planifolin to McCoy cells, tested in microculture with neutral red, showed a significant cytotoxic index (CI(50)) of 12.83 microg/mL. Planifolin showed mutagenic activity for TA100, TA98 and TA97a. The results indicate that this new naphthopyranone dimer causes mutations by substitution and by addition and deletion of bases in the sequence of DNA. Moreover, its mutagenic potential was increased by metabolic activation.