Tiazofurin Analogues Research Articles

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. The tiazofurin analogues were evaluated for their antitumour activities in cell-culture-based assays. Compounds 3, 4 (d-xylo) and 7 (d-arabino), showed remarkable antitumour activities, with IC50 values in the range of 4–7 nM. Preliminary structure-activity relationship allowed identification of two analogues with antiproliferative activities exceeding that of the parent compound 1 for several orders of magnitude (e.g. 4: 1354-fold against Raji, 7: 309-fold against K562). Flow cytometry data and Western blot analysis suggested that cytotoxic effects of d-xylo stereoisomers in the culture of K562 cells caused changes in the cell cycle distribution, as well as the induction of apoptosis in caspase-dependent way. The increase of apoptotic cells percentage in treated samples is also confirmed with fluorescent double-staining method. Genotoxicity testing showed that the analogues with the xylo-configuration (2–4) are far less genotoxic than tiazofurin.

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. Some of the synthesized compounds showed potent in vitro antitumour activity, such as 2′-azido derivative 2, which is the most potent of all molecules under evaluation (IC50 0.004 μM against MCF-7 cells). Flow cytometry data suggest that cytotoxic effects of these compounds in the culture of K562 cells might be mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of Western blot analysis indicate that the synthesized tiazofurin analogues induce apoptosis in a caspase-dependent way.

2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity

Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2–4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2–4 and 16) in K562 cells induced apoptosis in a caspase-dependent way.

ChemInform Abstract: Synthesis and in vitro Antitumor Screening of 2‐(β‐D‐xylofuranosyl)thiazole‐4‐carboxamide and Two Novel Tiazofurin Analogues with Substituted Tetrahydrofurodioxol Moiety as a Sugar Mimic.

AbstractThe known thiazofurin stereoisomer (VII) and two new thiazofurin analogues (XI) and (XII) are synthesized and evaluated for their in vitro antitumor activity.

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 (IC50=0.15μM) and HL-60 (IC50=0.13μM) cells. Flow cytometry data suggest that cytotoxic effects of analogue 2 in the culture of K562 cells might be mediated by apoptosis, in opposite to tiazofurin, which did not induce apoptosis of K562 cells after 24h, thus suggesting a different mechanism of action. All three analogues 2, 27 and 28 were also active against Jurkat, Raji and HeLa cells, with IC50 values in the range from 0.06 to 5.61μM, but were completely inactive against the normal foetal lung fibroblasts (MRC-5).

Antitumour tiazofurin analogues embedded with an amide moiety at the C-2′ position

Synthesis of four new tiazofurin analogues has been accomplished starting from d-glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3- O-acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b– d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d, while HeLa cells were sensitive to 2a, 2b and 2d. Only analogue 2a was highly cytotoxic against MCF-7 cells. No tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of tiazofurin analogues 2a– d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.

Synthesis and Antitumor Activity of New Tiazofurin Analogues Bearing a 2,3‐Anhydro Functionality in the Furanose Ring.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

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-β- dribofuranosyl)thiazole-4-carboxamide (2′,3′-anhydro-tiazofurin) and the corresponding α- and β-homo-C-nucleosides, as well as evaluation of their antitumour activities in vitro.

Synthesis and Antiproliferative Activity of Two New Tiazofurin Analogues with 2′‐Amido Functionalities.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis and antiproliferative activity of two new tiazofurin analogues with 2′-amido functionalities

Two novel tiazofurin analogues 2 and 3 were synthesized starting from d-glucose. The key step of the synthesis was the efficient one-step hydrogen sulfide-mediated conversion of 2-azido-3-O-acyl-ribofuranosyl cyanides to the corresponding 2-amido thiocarboxamides. Compounds 2 and 3 were evaluated for their in vitro antiproliferative activity against certain human tumour cell lines. Remarkably, compound 2 was found to be 570-fold more potent than tiazofurin against MCF-7 cells, while compound 3 showed the most powerful cytotoxicity against HT-29 cancer cells, being almost 100-fold more active than tiazofurin.

An efficient approach to enantiomeric isoxazolidinyl analogues of tiazofurin based on nitrone cycloadditions

An efficient synthetic route to isoxazolidinyl analogues of tiazofurin has been developed. The strategy involves, as a key step, a 1,3-dipolar cycloaddition between acrylonitrile and chiral nonracemic nitrones. An opposite diastereofacial induction was observed when the chiral group was placed at either the carbon atom or the nitrogen one of the nitrone function. The 2-cyano isoxazolidines obtained were further converted into the enantiomeric target compounds by constructing the thiazole ring via condensation with l-cysteine.

Ring‐Expanded C‐Nucleoside Analogues of Tiazofurin

Novel 1,3‐dioxane C‐nucleoside analogues of tiazofurin 2‐[2‐(hydroxymethyl)‐1,3‐dioxan‐5‐methyl‐5‐yl] 1,3‐thiazole‐4‐carboxamide, 2‐[2‐(hydroxymethyl)‐1,3‐dioxan‐5‐ethyl‐5‐yl] 1,3‐thiazole‐4‐carboxamide and 2‐[5‐(hydroxymethyl)‐1,3‐dioxan‐5‐methyl‐2‐yl] furan, 2‐[5‐(hydroxymethyl)‐1,3‐dioxan‐5‐methyl‐2‐yl] thiophen have been synthesized from DMPA and DMBA. Their conformational characteristics have been investigated.

Synthesis of novel 1,3‐dioxolane nucleoside analogues

AbstractNovel 1,3‐dioxolane C‐nucleoside analogues of tiazofurin 2‐(2‐hydroxymethyl‐1,3‐dioxolan‐4‐yl)‐l,3‐thiazole‐4‐carboxamide as well as N‐nucleoside analogues of substituted imidazoles 1‐(2‐hydroxymethyl‐1,3‐dioxolan‐4‐yl)‐4‐nitroimidazole and 1‐(2‐hydroxymethyl‐1,3‐dioxolan‐4‐yl)‐4,5‐dicyanoimidazole were synthesized from methyl acrylate through a multistep procedure. Their structures were confirmed by IR, 1H NMR, 13C NMR spectra and elemental analysis.

Synthesis and biological evaluation of two novel 2′-substituted tiazofurin analogues

Two novel tiazofurin analogues, 2-(2-benzamido-2-deoxy-β- d-ribofuranosyl)thiazole-4-carboxamide 4 and 2-(2-azido-2-deoxy-β- d-ribofuranosyl)thiazole-4-carboxamide 5 , have been synthesized starting from d-glucose and evaluated for their in vitro cytotoxicity against several human leukaemia and solid tumour cell lines.

Ring‐Expanded C‐Nucleoside Analogues of Tiazofurin

AbstractFor Abstract see ChemInform Abstract in Full Text.

De Novo Synthesis of Two New Cytotoxic Tiazofurin Analogues with Modified Sugar Moieties.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

Synthesis, conformational analysis, and biological activity of C-thioribonucleosides related to tiazofurin.

The syntheses of furanthiofurin [5beta-D-(4'-thioribofuranosyl)furan-3-carboxamide, 1] and thiophenthiofurin [5beta-D-(4'-thioribofuranosyl)thiophene-3-carboxamide, 2], two C-thioribonucleoside analogues of tiazofurin, are described. Direct trifluoroacetic acid-catalyzed C-glycosylation of ethyl furan-3-carboxylate with 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-ribofuranose gave 2- and 5-glycosylated regioisomers, as a mixture of alpha and beta anomers. Ethyl 5-(2,3,5-tri-O-benzyl)-beta-D-(4'-thioribofuranosyl)furan-3-carboxylate (6beta) was debenzylated and then converted into the corresponding amide (furanthiofurin) by reaction with ammonium hydroxide. A similar C-glycosylation of ethyl thiophene-3-carboxylate with 1,2,3,5-tetra-O-acetyl-4-thio-D-ribofuranose catalyzed by stannic chloride afforded an anomeric mixture of 2- and 5-glycosylated regioisomers. Deacetylation of ethyl 5-(2,3,5-tri-O-acetyl)-beta-D-(4'-thioribofuranosyl)thiophene-3-carboxylate (13beta) with methanolic ammonia and treatment of the ethyl ester with ammonium hydroxide gave thiophenthiofurin. The glycosylation site and anomeric configuration were established by (1)H NMR spectroscopy. Thiophenthiofurin was found to be cytotoxic in vitro toward human myelogenous leukemia K562, albeit 39-fold less than thiophenfurin, while furanthiofurin proved to be inactive. K562 cells incubated with thiophenthiofurin resulted in inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) and an increase in IMP pools with a concurrent decrease in GTP levels. From computational studies it was deduced that, among the C-nucleoside analogues of tiazofurin, activity requires an electrophilic sulfur adjacent to the C-glycosidic bond and an energetically favorable conformer around chi = 0 degrees. Among these, the more constrained (least flexible) compounds (tiazofurin and thiophenfurin) are more active than the less constrained thiophenthiofurin. Those compounds which contain a nucleophilic oxygen in place of the thiazole or thiophene (oxazofurin, furanfurin, and furanthiofurin) show the least activity.

Novel Mycophenolic Adenine bis(Phosphonate)S as Potent Anticancer Agents and Inducers of Cells Differentiation

An effective treatment of myeloid leukemias would rely on inducing myeloid cells to undergo differentiation. It has been demonstrated that inhibition of IMPDH with mycophenolic acid or tiazofurin resulted in inhibition of cell growth as well as induction of differentiation. We synthesized a number of bis(phosphonate) analogues of tiazofurin-, benzamide-, and mycophenolic-adenine dinucleotide which were found to be cytotoxic as well as effective inducers of cell differentiation.

ChemInform Abstract: Furanfurin (V) and Thiophenfurin (VI): Two Novel Tiazofurin Analogues. Synthesis, Structure, Antitumor Activity, and Interactions with Inosine Monophosphate Dehydrogenase.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.