RESUMO
The paper presents a detailed study of the biological effects of two amino acid hydroxyurea derivatives that showed selective antiproliferative effects in vitro on the growth of human tumor cell line SW620. Tested compounds induced cell cycle perturbations and apoptosis. Proteins were identified by proteomics analyses using two-dimensional gel electrophoresis coupled to mass spectrometry, which provided a complete insight into the most probable mechanism of action on the protein level. Molecular targets for tested compounds were analyzed by cheminformatics tools. Zinc-dependent histone deacetylases were identified as potential targets responsible for the observed antiproliferative effect.
Assuntos
Aminoácidos/química , Antineoplásicos/química , Hidroxiureia/análogos & derivados , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Eletroforese em Gel Bidimensional , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Proteoma/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
In the present paper, we report on the synthesis, and in vitro antiviral and cytostatic activities of a series of novel imidazole[4,5-e][1,3]diazepine-4,8-dione (compounds 9-11) and acyclic carbamoyl imino-ureido imidazole (compounds 12 and 13) derivatives. These new type of chemical entities showed no significant activity on the broad spectrum of DNA and RNA viruses. Results of antiproliferative assays performed on a panel of selected human tumor cell lines revealed that only compounds 1 and 5 showed moderate and selective cytostatic effect against HeLa cells (IC50 = 24 and 32 µM) with no concomitant cytotoxic effects on human normal fibroblasts (BJ). Importantly, an imidazole derivative containing a pyrrolidine moiety linked via an ethylenic spacer (3) showed a selective cytostatic effect toward cervical carcinoma (HeLa) cells (IC50 = 9.5 µM) with no apparent cytotoxicity on human normal fibroblasts (BJ). This compound can be therefore considered as a potential anti-tumor lead compound for further synthetic structure optimization.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Antineoplásicos/efeitos adversos , Antivirais/efeitos adversos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Vírus de DNA/efeitos dos fármacos , Células HeLa , Humanos , Imidazóis/efeitos adversos , Vírus de RNA/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC(50)s of 10 ± 4 and 7.3 ± 0.1 µM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on the host cell rather than with selective effect on the replication of the virus itself. In conclusion, results of this study put forward compound 6 as a potential novel antitumor agent (IMPDH inhibitor) for treating leukaemia. Its significant biological activity and low toxicity in human diploid fibroblasts encourage further development of this compound as a lead.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Ácido Ascórbico/análogos & derivados , Hepacivirus/efeitos dos fármacos , Imidazóis/química , Triazóis/química , Animais , Antineoplásicos/química , Antivirais/química , Ácido Ascórbico/química , Linhagem Celular Tumoral , Cães , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Hepacivirus/fisiologia , Humanos , IMP Desidrogenase/antagonistas & inibidores , Imidazóis/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Replicação Viral/efeitos dos fármacosRESUMO
We report here on the synthesis and in vitro anti-tumor effects of a series of novel 1,2,4-triazole (compounds 3-6), 4,5-dicyanoimidazole (compound 7), and purine (compounds 8-13) coumarin derivatives and their acyclic nucleoside analogues 14-18. Structures of novel compounds 3-18 were deduced from their (1)H- and (13)C-NMR and corresponding mass spectra. Results of anti-proliferative assays performed on a panel of selected human tumor cell lines revealed that compound 6 had moderate cytostatic activity against the HeLa cell line (IC(50) = 35 µM), whereas compound 10 showed moderate activity against the HeLa (IC(50) = 33 µM), HepG2 (IC(50) = 25 µM) and SW620 (IC(50) = 35 µM) cell lines. These compounds showed no cytotoxic effects on normal (diploid) human fibroblasts.
Assuntos
Antineoplásicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Imidazóis/química , Purinas/química , Triazóis/química , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Neoplasias/tratamento farmacológico , Nucleosídeos/química , Relação Estrutura-AtividadeRESUMO
We report on the synthesis of 4-hydroxycoumarin dimers 1-15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16-20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1-20 were deduced from their homo- and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The X-ray crystal structure analysis revealed that two 4-hydroxycoumarin moieties in the 4-trifluoromethylphenyl- and 2-nitrophenyl derivatives (compounds 7 and 9, respectively) are intramolecularly hydrogen-bonded between hydroxyl and carbonyl oxygen atoms. Consequently, the compounds 7 and 9 adopt conformations in which two 4-hydroxy-coumarin moieties are anti-disposed. Antiviral activity evaluation results indicated that the 4-bromobenzylidene derivative of bis-(4-hydroxycoumarin) (compound 3) possesses inhibitory activity against HSV-1 (KOS), HSV-2 (G), vaccinia virus and HSV-1 TKâ» KOS (ACVr) at a concentration of 9-12 µM and at a minimum cytotoxic concentration (MCC) greater than 20 µM. Compounds 4-6, 8, and 20 were active against feline herpes virus (50% effective concentration, EC50 = 5-8.1 µM), that is at a 4-7-fold lower concentration than the MCC.
Assuntos
4-Hidroxicumarinas/química , Antivirais/química , Antivirais/farmacologia , Cumarínicos/química , Espectroscopia de Ressonância Magnética/métodos , Difração de Raios X/métodos , Animais , Gatos , Linhagem Celular , Linhagem Celular Tumoral , Cães , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Estrutura MolecularRESUMO
A series of the novel acyclic unsaturated pyrimidine (1-12) and adenine (13) nucleoside analogues bearing conformationally restricted (Z)-2'-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative (11), N-1, N-3 disubstituted 5-fluorouracil derivative (12) and adenine derivative (13) was deduced from their (1)H and (13)C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11-13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1-13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 microM). Of all evaluated compounds on the cell lines tested only the N-1 4''-fluoro-substituted-benzamide uracil derivative (7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 microM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/química , Antivirais/química , Nucleosídeos/química , Nucleosídeos/farmacologia , Pirimidinas/química , Adenina/química , Adenina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi , Humanos , Isomerismo , Estrutura Molecular , Nucleosídeos/síntese química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of the novel C-5 alkynyl pyrimidine nucleoside analogues (1-14) in which the sugar moiety was replaced by the conformationally restricted Z- and E-2-butenyl spacer between the phthalimido and pyrimidine ring were synthesized by using Sonogashira cross-coupling reaction. Cytostatic activity evaluation of the novel compounds showed that E-isomers exhibited, in general, better cytostatic activities than the corresponding Z-isomers. E-isomer 14 exhibited the best cytostatic effect against all evaluated malignant cell lines, particularly against hepatocellular carcinoma (Hep G2, IC(50)=4.3microM). However, this compound was also cytotoxic to human normal fibroblasts (WI 38). Its Z-isomer 7 showed highly specific antiproliferative activity against Hep G2 (IC(50)=18microM) and no cytotoxicity to WI 38. Moreover, compounds 3, 4 and 14 expressed some marginal inhibitory activity against HIV-1 and HIV-2.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Leucemia L1210/tratamento farmacológico , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Animais , Fármacos Anti-HIV/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Células HeLa , Humanos , Leucemia L1210/patologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The novel C-5 alkynyl substituted pyrimidine (1-11) and furo[2,3-d]pyrimidine derivatives (12-22) of l-ascorbic acid were synthesized by coupling of 5-iodouracil-4',5'-didehydro-5',6'-dideoxy-l-ascorbic acid with terminal alkynes by using Sonogashira cross-coupling reaction conditions. The new compounds were evaluated for their cytostatic and antiviral activities. Among all evaluated compounds, the octynyl-substituted uracil derivative of l-ascorbic acid (3) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC50 = 2-12 microM). Pyrimidine derivatives of l-ascorbic acid containing p-substituted phenylacetylene groups (8-11) displayed also a rather pronounced (IC50 = 3-37 microM) inhibitory effect toward all tumor cell lines. From the bicyclic series of compounds, 6-butylfuro[2,3-d]pyrimidine derivative (12) and 6-p-bromophenylfuro[2,3-d]pyrimidine derivative (19) showed the highest cytostatic activity (IC50 = 4.5-20 microM), particularly against malignant leukemia (L1210) and T-lymphocyte (Molt4/C8 and CEM) cells. Compounds 3 and 9 showed specific albeit moderate activity against cytomegalovirus (CMV, Davis strain, EC50 = 1.8 and 3.8 microM, respectively, for compounds 3 and 9) at a approximately 5-fold lower concentration than that required to show cytotoxicity.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/síntese química , Pirimidinas/síntese química , Pirimidinonas/síntese química , Animais , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ácido Ascórbico/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Pirimidinas/farmacologia , Pirimidinonas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthetic route for introduction of a fluoroalkyl (7-12, 14), fluoroalkenyl (15 and 16), fluorophenylalkyl (17, 19, 20, and 22), and fluorophenylalkenyl (18, 21) side chain at C-6 of the pyrimidine involved the lithiation of the pyrimidine derivatives 3 and 3a and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with various electrophiles. Conformational properties of the novel fluorinated pyrimidine derivatives were assessed by the use of 1D difference NOE enhancements and C-F coupling constants. Compounds 4-22 were evaluated for their antiviral and cytostatic activities. Of all compounds evaluated, the 5-bromopyrimidine derivatives 5 and 6 showed the highest inhibitory activities. Among the series of fluoroalkylated pyrimidines, which is generally more active than the series of fluorophenylalkylated pyrimidines, compounds 8 and 14 displayed moderate cytostatic activities against the tested tumor cell lines. Moreover, compound 8 containing a 2-fluoromethylpropyl side chain expressed some but not highly specific activity against varicella-zoster virus (VZV). From C-6 fluorophenylalkylated pyrimidine derivatives, 17a and 21 showed a slight activity against cytomegalovirus (CMV), VZV, and Coxsackie B4 virus, respectively. Besides, compounds 17a and 21 showed no cytotoxic effect.
Assuntos
Antivirais/síntese química , Citostáticos/síntese química , Pirimidinas/síntese química , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Citostáticos/química , Citostáticos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Tomografia por Emissão de Pósitrons , Nucleosídeos de Pirimidina/química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The 5,6-di-O-tosylated derivative of l-ascorbic acid was synthesized by selective protection and deprotection of 2,3- and 5,6-dihydroxy functional groups involving 5,6-ditosylation in the final step, while the novel 6-acetoxy, 6-hydroxy, and 6-chloro derivatives of 4,5-didehydro-l-ascorbic acid were obtained by reaction of ditosylated compound with nucleophilic reagents. The analysis of 3JH-4-H-5 homonuclear coupling constants shows that all l-ascorbic acid derivatives except for epoxy and 4,5-didehydro compounds exist in high population as gauche conformers across C-4-C-5 bonds, while 3JC-3-H-5 heteronuclear coupling constants in 4,5-didehydro derivatives indicate cis geometry along C-4-C-5 double bond. The X-ray crystal structure analysis of 2,3-di-O-benzyl-5,6-epoxy- and 5,6-isopropylidene-l-ascorbic acid shows that the oxygen atoms attached at positions 2 and 3 of the lactone ring are disposed in a synperiplanar fashion. Besides that, the dioxolane ring adopts half-chair conformation. The molecules of epoxy derivative are joined into infinite chains by one weak hydrogen bond of C-H...O type. Two O-H...O, and C-H...O hydrogen bonds link the molecules of 5,6-di-O-isopropylidene compound into two-dimensional network. 6-Chloro derivative of 2,3-di-O-benzyl-l-ascorbic acid showed the best cytostatic effects against all tested malignant tumor cells (IC50: approximately 18 microM).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ácido Ascórbico/síntese química , Ácido Ascórbico/farmacologia , Antineoplásicos/química , Ácido Ascórbico/análogos & derivados , Configuração de Carboidratos , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
3,5-Disubstituted hydantoin (1,3-imidazolidinedione) derivatives 5a-h were prepared by base induced cyclization of the corresponding N-(1-benzotriazolecarbonyl)-L- and D-amino acid amides 4a-h. Compounds 5a-h were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, 3-benzhydryl-5-isopropyl hydantoin (5a) showed a weak but selective inhibitory effect against vaccinia virus (EC(50) = 16 microg/mL; selectivity index: 25). 3-Cyclohexyl-5-phenyl hydantoin (5g) showed inhibitory activity against cervical carcinoma (HeLa, IC(50) = 5.4 microM) and breast carcinoma (MCF-7, IC(50) = 2 microM), but also cytotoxic effects towards human normal fibroblasts (WI 38). On the contrary, the 3-benzhydryl-5-phenyl substituted hydantoin derivative 5h showed moderate inhibitory activity towards HeLa, MCF-7, pancreatic carcinoma (MiaPaCa-2), lung carcinoma (H 460) and colon carcinoma (SW 620) (IC(50) = 20-23 microM), but no effect on WI 38.
Assuntos
Aminoácidos/síntese química , Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Hidantoínas/síntese química , Hidantoínas/farmacologia , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Hidantoínas/química , Espectroscopia de Ressonância Magnética , Vírus/efeitos dos fármacosRESUMO
In vitro evaluation of the novel cycloalkyl-N-(4-chlorophenyl)-hydroxamic acids (2a-g) demonstrated that 2b,d,e exhibited rather marked inhibitory activity (IC50 = 7-10 microM) against pancreatic carcinoma, 2b-d against colon carcinoma, 2d against laryngeal carcinoma, and 2b,d against breast carcinoma. 2e showed the most pronounced anti-cytomegalovirus activity (EC50 = 1.5 and 0.8 microg mL(-1)) only at > or = 5-fold lower than the cytotoxic concentration. 2d and 2f showed modest, albeit selective, activity against cytomegalovirus (2d, EC50 = 7.3-8.9 microg mL(-1), selectivity index 7-10; 2f, EC50 = 7-13 microg mL(-1), selectivity index 10).
Assuntos
Acetamidas/síntese química , Adamantano/análogos & derivados , Adamantano/síntese química , Antineoplásicos/síntese química , Antivirais/síntese química , Ácidos Hidroxâmicos/síntese química , Acetamidas/química , Acetamidas/farmacologia , Adamantano/química , Adamantano/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Citomegalovirus/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The novel L- and D-amino acid derivatives of hydroxyurea 5a-o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a-o with hydroxylamine. The hydantoin derivatives 6a-e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among L-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC(50) = 10-19 microM) and showed selectivity with respect to normal human fibroblasts (WI 38). d-Amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC(50) = 4.8-83.9 microM), but not the growth of normal fibroblasts (WI 38; IC(50) > 100 microM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC(50) = 3.2 microg/mL; 6m, EC(50) = 4.0 microg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC(50) = 43.4 microg/mL; 6m, CC(50) = 12.5 microg/mL(-1)).
Assuntos
Aminoácidos/síntese química , Antineoplásicos/síntese química , Antivirais/síntese química , Hidantoínas/síntese química , Hidroxiureia/análogos & derivados , Hidroxiureia/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Citomegalovirus/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Hidantoínas/química , Hidantoínas/farmacologia , Hidroxiureia/química , Hidroxiureia/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of the novel 5-methyl pyrimidine derivatives with an acyclic side chain at the C-6 position were synthesized using lithiation of a 2,4-dimethoxy-5,6-dimethyl pyrimidine and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with acetaldehyde, epichlorhydrine, fluorinated ketones and fluorinated ester. The novel compounds were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, two fluorinated acyclic pyrimidine derivatives showed the highest cytostatic activities. The compound containing a 2-hydroxy-3,3,3-trifluoro-1-propenyl side chain exhibited a pronounced effect against breast carcinoma (MCF-7, IC50=8.38 micorg/ml), while the compound with a 2-fluoromethyl-2-acetoxypropyl chain exhibited moderate effect against cervical carcinoma (HeLa, IC50=19.73 microg/ml).
Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Timina/química , Timina/farmacologia , Antineoplásicos/química , Antivirais/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade MicrobianaRESUMO
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and l-ascorbic acid (l-AA) in mind, we have synthesized new 3-, 7- and 9-deazapurine derivatives of l-ascorbic (1-4, 8-10, 13-15) and imino-l-ascorbic acid (5-7, 11, 12, 16-19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of l-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC50 = 4.1 ± 1.8 µM) and strong antiproliferative effect against L1210/0 (IC50 = 4.7 ± 0.1 µM) while the 9-deazahypoxanthine derivative of l-AA (15) showed the best effect against HeLa cells (IC50 = 5.6 ± 1.3 µM) and prominent effect on L1210/0 (IC50 = 4.5 ± 0.5 µM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-l-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC50 = 4.4 ± 0.3 µM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC50 = 5.7 ± 0.2 µM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3-deazapurine derivative of l-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.
Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Citomegalovirus/efeitos dos fármacos , Purinas/química , Purinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Ácido Ascórbico/síntese química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Purinas/síntese química , Relação Estrutura-AtividadeRESUMO
The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (1a-7a and 9a-13a) and 9-(2-hydroxyethoxymethyl) (1b-3b, 5b, and 7b-12c) side chains were synthesized by a multistep synthetic route involving Baltz-Schiemann's fluorination and diazotation/iodination as key reactions. An unequivocal proof for the stereostructure of 5b was obtained by X-ray structure analysis. New compounds were evaluated for their cytostatic activity against murine leukemia (L1210); mammary carcinoma (FM3A); and human T-lymphocytes (Molt4/C8 and CEM), melanoma (HBL), cervical carcinoma (HeLa), colon carcinoma (HT29 and SW620), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2) as well as diploid fibroblasts (WI38). Of all the compounds, the 2-aminopurin-6-thione derivative 9a showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative 9b exhibited the most selective inhibitory activity against human HeLa, Hep2, SW620, and murine L1210 cell proliferation as compared to normal fibroblast (WI38) cell proliferation. None of the compounds showed inhibitory activities against HIV-1, HIV-2, HSV-1, and HSV-2, vaccinia, vesicular stomatitis, parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, or respiratory syncytial virus. The new purine derivatives, and particularly 9a and 9b, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Flúor , Guanina/síntese química , Iodo , Nucleosídeos de Purina/síntese química , Tionas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Guanina/análogos & derivados , Guanina/química , Guanina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Tionas/química , Tionas/farmacologiaRESUMO
The novel purine derivatives of 1-aminocyclopropane-1-carboxylic acid (8 and 9) and 1-amino-1-hydroxymethylcyclopropane (12 and 13) with methylene spacer between the base and the cyclopropane ring were prepared by multistep synthetic route involving alkylation of adenine and 6-(N-pyrrolyl)purine with 2-hydroxy-methyl-1-aminocyclopropane-1-carboxylic acid derivative 3 as a key reaction. All novel compounds were racemic. The N-9 substitution of the purine ring and the Z-configuration of the cyclopropane ring in 4-13 were deduced from their 1H and 13C NMR spectra by analyses of chemical shifts, H-H coupling constants and connectivities in two-dimensional homo- and heteronuclear correlation spectra. An unequivocal proof of the stereostructure of 1, 4 and 5 was obtained by their X-ray structure analysis. The novel compounds were evaluated on cytostatic and antiviral activities in several cell lines. The 6-(N-pyrrolyl)purine derivative of 1,2-aminocyclopropane alcohol 12 exhibited a more pronounced inhibitory activity against the proliferation of cervical carcinoma (HeLa) and human fibroblast (WI-38) cells than other types of tumor cell lines. None of the compounds showed inhibitory activities against cytomegalovirus, varicella-zoster virus or other viruses.
Assuntos
Aminoácidos Cíclicos/química , Antineoplásicos , Antivirais , Ciclopropanos/química , Purinas/química , Aminoácidos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , CamundongosRESUMO
BACKGROUND: Several published studies indicate that the acyclic guanine nucleoside analogues possessing bis(1,2-hydroxymethyl) substituted cyclopropane rings mimicking the sugar moiety are potent inhibitors of replication of several herpes viruses. METHODS: Established synthetic methods and antiviral and cytostatic activity assays were used for the evaluation of new 1,2,4-triazole and purine acyclic nucleoside analogues. RESULTS: The synthesis of new types of acyclic nucleoside analogues which incorporate 1,2,4-triazole or purine moiety bound via flexible methylenic spacer to the bis(1,2-hydroxymethyl) cyclopropane ring. None of the new compounds showed pronounced antiviral activities at subtoxic concentrations on a broad panel of DNA and RNA viruses. Evaluation of their affinity for herpes simplex type 1 (HSV-1) and varicella-zoster virus-encoded thymidine kinases (VZV TK) also showed that none of the compounds was able to significantly inhibit 1 µM deoxythymidine phosphorylation by HSV-1 and VZV TK at 500 µM concentrations. The in vitro cytostatic activity evaluation results indicated a weak antiproliferative activity for all tested compounds. Only 6-pyrrolylpurine derivative bearing a carboxylic group substituted cyclopropane ring produced a rather slight inhibitory effect at higher micromolar concentrations on a breast carcinoma cell line (MCF-7) and no cytotoxic effect on human normal fibroblasts (WI 38). CONCLUSIONS: The lack of antiherpetic activity may be due to poor, if any, recognition of the compounds by virus-induced nucleoside kinases as an alternative substrate to become metabolically activated.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citostáticos/síntese química , Citostáticos/farmacologia , Nucleosídeos de Purina/química , Animais , Antivirais/química , Linhagem Celular Tumoral , Células Cultivadas , Citostáticos/química , Vírus de DNA/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Herpesvirus Humano 1/enzimologia , Herpesvirus Humano 3/enzimologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fosforilação , Nucleosídeos de Purina/farmacologia , Vírus de RNA/efeitos dos fármacos , Relação Estrutura-Atividade , Timidina/metabolismo , Timidina Quinase/antagonistas & inibidores , Triazóis/químicaRESUMO
AIM: Several published studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are promising anticancer agents. This study examined the in vitro effect of O-alkylated NSAID hydroxamic acid derivatives 3a-i on cell survival for a panel of human tumour cell lines, their cytotoxicity on normal human fibroblasts and their antiviral activity. MATERIALS AND METHODS: Established methods of cell viability testings, cell cycle analyses and Western blot assays were used. RESULTS: O-Alkylated NSAID hydroxamic acid derivatives exerted poor antiviral activity butreduced the viability of the studied tumour cell lines in a concentration-dependent manner showing low cytotoxic effect on normal fibroblasts. Compounds 3a and 3i were shown to be potent inhibitors of the growth of MIA PaCa-2 cell line. They induced p53-independent S-phase arrest and triggered caspase 3-dependent apoptosis. CONCLUSION: Two novel O-alkylated NSAID hydroxamic acid derivatives may be useful in the treatment of pancreatic cancer and should be further evaluated in vivo.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Hidroxâmicos/farmacologia , Animais , Antineoplásicos/farmacologia , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Leucemia L1210/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Non-steroidal anti-inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a-i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7-10. On the other hand, the results of the in vitro cytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives 3a-i exhibited a strong non-specific antiproliferative effect at the highest concentration (100 microM) on the tested cell line panel. Only compounds 3b, 3e and 3i exerted a differential dose-dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 microM. Among those three compounds, only compound 3b showed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.