No abstract

We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

No abstract

The conformation and configuration analysis of the dimer bis(N,N-dimethyl-2,4-dimethylglutarylamide) was carried out by means of both conventional 1H and 13C NMR spectroscopy and advanced (INEPTLR and 2D HETCOR) methods. The γ-gauche effect method appears to reproduce the observed chemical shift difference between m- and r-isomers. Stereochemical structure of poly(N,N-dimethylacrylamide) (PDMAA) was studied using proton spectrum (at the triad level) and DEPT spectra (at the triad and pentad level). For PDMAA prepared by radical polymerization, the Bernoullian statistics are required to fit the observed intensities at the pentad level.

The oxidative cyclization of (E,E)‐2′‐hydroxycinnamylideneacetophenones 1a–e, and (E, E)‐2′‐benzyloxy‐6′‐hydroxycinnamylideneacetophenones 1i–l with DMSO/iodine, gave (E)‐2‐styrylchromones 3a–e,i–l. However, in the case of (E, E)‐γ‐alkyl‐2′‐hydroxycinnamylideneacetophenones 1f–h, (E)‐ and (Z)‐2‐styrylchromones 3f–h and 4f–h were obtained. The stereochemistry of the (E,E)‐cinnamylideneacetophenones 1 and (E)‐ and (Z)‐2‐styrylchromones 3 and 4 was established by NOE experiments. The induced daylight photooxidative cyclization of some (E)‐2‐styrylchromones 3a,f–h gave 12H‐benzo[a]xanthene‐12‐ones 6a,f–h.