Aldo Andreani

New antitumor imidazo[2,1-b]thiazole guanylhydrazones and analogues.

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.

Antitumor Activity of Bis-Indole Derivatives

This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.

Antitumor Activity of New Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-Imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones : Selectivity against Colon Tumor Cells and Effect on Cell Cycle-Related Events

The synthesis of new 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones is reported. The antitumor activity was evaluated according to the protocols available at the National Cancer Institute (NCI), Bethesda, MD. To investigate the mechanism of action of the most potent antitumor agent of this series, its effect on growth of HT-29 colon carcinoma cells was studied. Its ability to inhibit cellular proliferation was mediated by cell cycle arrest at the G2/M phase, accompanied by inhibition of ornithine decarboxylase (ODC), the limiting enzyme of polyamine synthesis, and followed by induction of apoptosis.

Potential antitumor agents. part 291: synthesis and potential coanthracyclinic activity of Imidazo[2,1-b]thiazole guanylhydrazones

This paper reports the synthesis of new imidazo[2,1-b]thiazole guanylhydrazones which were tested as potential antitumor agents. Three of these derivatives (those bearing a 3- or 4-nitrophenyl group) were the most potent and one of these showed a mild effect as CDK1 inhibitor. These same three derivatives were also tested as positive inotropic agents and two of them were more potent than amrinone at 10(-5) M. These two guanylhydrazones could be useful coanthracyclinic agents.

Synthesis and diuretic activity of imidazo[2,1-b]thiazole acetohydrazones

Abstract The synthesis of dimethylaminoacetohydrazones of 5-formylimidazo[2,1-b]thiazoles and thiazolines is reported. A potent diuretic activity was confirmed for the 2-methyl derivative bearing a phenyl ring at position 6 (4 1 ).

Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and Analogues: Synthesis, Cytotoxic Activity and Study of the Mechanism of Action

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.

Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors.

The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells.

Synthesis and cardiotonic activity of imidazo[2,l-b]thiazoles bearing a lactam ring

Summary This paper describes the synthesis of 6-substituted imidazo[2,1- b ]thiazoles with a lactam ring connected, by means of a methine group, to the 5-position. The pharmacological results show that interesting cardiotonic activity is obtained when the lactam ring is pseudothiohydantoin ( 8 ) or barbituric acid ( 9 ). Even the substituent at position 6 plays an important role in the pharmacological behavior of these derivatives. The following activity rank order was observed: phenyl > methyl > chlorine.

New isatin derivatives with antioxidant activity

The reaction between isatin and 2,5-dimethoxyaniline is described. The main product was identified as 3,3-bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one. The antioxidant activity of the compounds isolated was evaluated with two methods. Three published antitumor E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones entered the same tests to search whether they are endowed with antioxidant activity too. 3,3-Bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one and the three antitumor agents showed a good chemical antioxidant activity.

Potential anti-tumor agents XVI. Imidazo[2,1-b]thiazoles

Abstract A number of imidazo[2,1-b]thiazoles have been synthesized and tested in mice bearing Ehrlich ascites tumor cells. The nitrogen mustard 5 had a T C of 140 at 8 mg/kg.