RESUMO
The synthesis of several new goniofufurone bioisosteres was achieved in which the phenyl residue was replaced by a thiazole ring. The key steps of the synthesis included the initial condensation of cyanohydrin benzoates with cysteine ethyl ester hydrochloride, followed by the subsequent reaction of resulting C-4' epimeric thiazolines with DBU, to introduce 5-deoxy functionality and to elaborate the thiazole ring in one step. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially bioisostere 4, which in the culture of MCF-7 cells displayed the highest activity (IC50 = 0.19 nM) of all compounds under evaluation. This molecule exhibited 64474-fold higher antiproliferative activity than lead 2 and was1053-fold more active than the commercial antitumour agent doxorubicin in the culture of MCF-7 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis. The toxicity of the most active compound 4 was assessed by an in vivo experiment in a zebrafish model (Danio rerio), whereupon it was found non-toxic at any of the tested concentrations up to 125 µM.
Assuntos
Antineoplásicos , Tiazóis , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Peixe-ZebraRESUMO
2-(ß-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)=0.13 µM) 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 IC(50) values in the range from 0.06 to 5.61 µM, but were completely inactive against the normal foetal lung fibroblasts (MRC-5).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Nucleosídeos/síntese química , Ribavirina/análogos & derivados , Antineoplásicos/química , Carboidratos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Mimetismo Molecular , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/farmacologia , Ribavirina/síntese química , Ribavirina/química , Ribavirina/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Xilose/químicaRESUMO
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 4-7â¯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 K562â¯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.
Assuntos
Antineoplásicos , Desenho de Fármacos , Ribavirina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células K562 , Nitrogênio/química , Ribavirina/síntese química , Ribavirina/química , Ribavirina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ribavirina/análogos & derivados , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ribavirina/síntese química , Ribavirina/química , Ribavirina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ribavirina/análogos & derivados , Antineoplásicos/química , Furanos/química , IMP Desidrogenase/antagonistas & inibidores , Ribavirina/síntese química , Ribavirina/química , Ribavirina/farmacologiaRESUMO
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.
Assuntos
Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Ribavirina/análogos & derivados , Linhagem Celular Tumoral , Humanos , Ribavirina/síntese química , Ribavirina/química , Ribavirina/farmacologiaRESUMO
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. 2-, 27- and 17-fold lower than those observed for tiazofurin. Remarkably, compound 3 did not exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cell line.