Structure based design, synthesis and in vitro antitumour activity of tiazofurin stereoisomers with nitrogen functions at the C-2' or C-3' positions.

Three novel tiazofurin analogues having d-arabino stereochemistry and nitrogen functionalities at the C-2' position (5-7) have been designed and synthesized in multistep sequences, starting from d-glucose. The known d-xylo stereoisomer of 1 (compound 2) along with two new analogues bearing nitrogen functions at the C-3' (3 and 4) has also been synthesized from the same sugar precursor. The synthetic sequence consisted of the following three stages: (i) the multistep synthesis of suitably protected pentofuranosyl cyanides, (ii) the construction of ethyl thiazole-4-carboxylate part by cyclocondensation of thus obtained glycofuranosyl cyanides with l-cysteine ethyl ester followed by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylates into the target tiazofurin analogues using the esters ammonolysis.

Synthesis and in vitro antitumour activity of tiazofurin analogues with nitrogen functionalities at the C-2' position.

Synthesis of three tiazofurin (1) isosteres with nitrogen functionalities at the C-2' position (N3, NH2 and NH3(+)Cl(-)) has been achieved, in multistep sequences, starting from monoacetone d-glucose. A number of potential bioisosteres of 1 bearing acylamido functions at the C-2' position have also been synthesized from the same sugar precursor. In vitro cytotoxicities of target molecules against a number of human tumour cell lines were recorded and compared with those observed for lead molecule 1.

Synthesis and in vitro antitumour screening of 2-(β-D-xylofuranosyl)thiazole-4-carboxamide and two novel tiazofurin analogues with substituted tetrahydrofurodioxol moiety as a sugar mimic.

2-(β-D-xylofuranosyl)thiazole-4-carboxamide (2) and two new tiazofurin analogues with 5-hydroxymethyl-2-methyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (27 and 28) have been synthesized and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines (K562, HL 60, Jurkat, Raji and HeLa). In contrast to previous literature reports, a metabolic MTT assay revealed remarkable cytotoxicity of 2 against K562 (IC(50)=0.15 μM) and HL-60 (IC(50)=0.

Synthesis and antitumour activity of new tiazofurin analogues bearing a 2,3-anhydro functionality in the furanose ring.

This paper describes a divergent de novo synthesis of 2-(2,3-anhydro-beta-dribofuranosyl)thiazole-4-carboxamide (2',3'-anhydro-tiazofurin) and the corresponding alpha- and beta-homo-C-nucleosides, as well as evaluation of their antitumour activities in vitro.

2-(3-Amino-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide: a new tiazofurin analogue with potent antitumour activity.

A new tiazofurin analogue, 2-(3-amino-3-deoxy-beta-d-xylofuranosyl)thiazole-4-carboxamide (3), was synthesized starting from d-glucose and evaluated for its in vitro antiproliferative activity against a panel of human tumour cell lines. Compound 3 exhibited the most powerful cytotoxicity against K562 cells, being approximately 100-fold more potent than tiazofurin. This analogue was also active against Jurkat, HT-29 and HeLa malignant cells, with respective IC(50) values being ca.

De novo synthesis of two new cytotoxic tiazofurin analogues with modified sugar moieties.

A divergent synthesis of two novel tiazofurin analogues, 2-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)thiazole-4-carboxamide (2) and 2-(3-acetamido-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide (3), has been achieved starting from D-glucose. Both nucleoside analogues were evaluated for their in vitro cytotoxicity against several human leukaemia and solid tumour cell lines.

Evaluation of left ventricular diastolic function by radionuclide ventriculography in patients with coronary artery disease.

Radionuclide ventriculography (RNV) was used to assess the peak filling rate (PFR) in 20 patients with coronary artery disease (CAD). Dipyridamole RNV was used in 5 normal subjects and 10 patients with CAD with the view to evaluating PFR increase. Significant difference in PFR values was established between normal subjects and CAD patients.