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The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly.

The synthesis of new substituted E-3-(3-indolylmethylene)1,3-dihydroindol-2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure-activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and lastly activation of apoptosis.

The synthesis of new antitumor 6-substituted imidazothiazole guanylhydrazones is described. Moreover, a series of compounds with a different basic chain at the 5 position were prepared. Finally, the replacement of the thiazole ring in the imidazothiazole system was also considered. All the new compounds prepared were submitted to the NCI cell line screen for evaluation of their antitumor activity. A few selected compounds were submitted to additional biological studies concerning effects on the cell cycle, apoptosis, and mitochondria.

Extended survival of clonal hematopoietic progenitors associated with the bcr-abl expression has a key role in the pathogenesis of Chronic Myeloid Leukemia (CML) and may concur to promote the disease progression towards the fully transformed, drug-resistant phenotype of blast crisis. Here we demonstrated that p210 bcr-abl protein tyrosine kinase (TK) activity protects bcr-abl-transducing 32D cell clones from apoptotic death through multiple pathways preserving mitochondrial membrane integrity. P210 TK prevents Trail/DR4, Bim and Bax induction and caspase 9 and Bid activation and upregulates the expression of anti-apoptotic BclxL in the cytoplasm. Moreover, it precludes the integration and aggregation of pro-apoptotic signals Bid, Bax and Bak at mitochondrial membranes letting, in turn, pore opening and apoptogenic molecule leakage from intermembrane spaces. Our results underscore the central role of Akt serine/threonine kinase, activated by p210 TK downstream of phosphatidyl-inositol 3 kinase (PI3K), in leukemic progenitor failure to undergo apoptotic death and support that pharmacological targeting of its enzymatic activity may implement the effects of TK inhibitor Imatinib mesylate (IM).