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Activation of Wnt signalling due to inability to degrade β-catenin is found in >85% of colorectal cancers. Approximately half of colon cancers express a constitutively active KRAS protein. A significant fraction of patients show both abnormalities. We previously reported that simultaneous down-regulation of both β-catenin and KRAS was necessary to induce significant cell death and tumor growth inhibition of colorectal cancer cells. Although attractive, an RNAi-based therapeutic approach is still far from being employed in the clinical setting. Therefore, we sought to recapitulate our previous findings by the use of small-molecule inhibitors of β-catenin and KRAS. We show here that the β-catenin inhibitors PKF115-584 and pyrvinium pamoate block β-catenin-dependent transcriptional activity and synergize with the KRAS inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in colon cancer cells driven by Wnt and KRAS oncogenic signals, but not in cells carrying BRAF mutations. The combined use of these compounds was superior to the use of any drug alone in inducing cell growth arrest, cell death, MYC and survivin down-modulation, and inhibition of anchorage-independent growth. Expression analysis of selected cancer-relevant genes revealed down-regulation of CD44 as a common response to the combined treatments. These data provide a proof of principle for a combination therapeutic strategy in colorectal cancer.

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BackgroundResistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosomepositive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584).

H e x a c h l o r o b e n z o t r i n o r b o r n a d i e n e f o r t h e C o n s t r u c t i o n o f M o l e c u l a r D o m e sAbstract: Well-defined, rigid molecular domes are obtained via substitution of the chlorine atoms of hexachlorobenzotrinorbornadiene syn-3, efficiently synthesized in 1:2 ratio along with its antiisomer by CuTC-promoted cyclotrimerization of 3-bromo-2-trimethylstannylnorbornadiene 8. The three dichlorovinyl functions at the edge of syn-3 are displaced by sulfur nucleophiles and Grignard reagents with Ni(II)Cl 2 dppe as catalyst, gaining the persubstituted vinyl sulfides 9 and 10, and persubstituted methyl 12 and phenylethynyl 13.Structures in which a benzene ring is embedded in a molecular framework, functionalized only on one side of the aromatic plane, are attractive cores for the construction of larger molecular architectures, such as dendrimers and discotic liquid crystals. The structure sketched by the formula syn-1 (Scheme 1), with six reactive functionalities at the edge, combines the proprieties of concavity and rigidity with the possibility of different derivatizations. Scheme 1We have recently shown 1,2 that similar structures can be quantitatively obtained by the cyclotrimerization reaction of the appropriate monomer 2, functionalized at the vinyl end by bromine and trimethylstannyl groups, via the promotion of copper(I) 2-thiophenecarboxylate (CuTC). 3 We have also explored the reactivity in Diels-Alder reactions of one functionalized syn cyclotrimer with three diene systems at the edge. 2 The cyclotrimerization reaction affords both the syn-1 and the anti-1 isomers. The development of this project requires high yield in the first isomer, possibly exceeding the 1:3 syn/anti statistical ratio.We report in this paper the synthesis of the syn-3 and anti-3 cyclotrimers, characterized by the presence of three dichlorovinyl moieties. Among the synthetic uses of these substrates, the formations of C-S bonds from aliphatic and aromatic thiols, and of new C-C bonds through the use of metal-catalyzed cross-coupling are explored.The syn-3 and anti-3 cyclotrimers were obtained by the synthetic sequence illustrated in Scheme 2. Because of the high reaction temperature, the Diels-Alder addition of trichloroethylene to cyclopentadiene 4 does not require the formation of the latter by distillation of the cyclopentadiene dimer. Although the yield of the two isomers 5 is rather low, the inexpensive reagents make this step economically attractive. The bromination with molecular bromine is not stereoselective, and no Wagner-Meerwein rearrangement was observed. 5 The mixture of adducts 6 is then dehydrohalogenated with t-BuOK, gaining 7 as single product. The stannylation with Me 3 SnCl and LDA gives the monomer 8, and is followed by the action of CuTC. The syn-3 and anti-3 isomers, obtained with a 90% yield and in 1:2 ratio, have been separated by flash chromatography. 6 This straightforward synthetic path, which does not require particular purifications, afforded the two isomers of 3 in mu...