RESUMEN
In this review a short account of our work on the synthesis and biological activity of electrically neutral and charged anti-HIV and anticancer pronucleotides, presented on the background of the contemporary research in this area, is given.
RESUMEN
We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118â¯MG, U-87â¯MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2â¯cell line), and may be considered as potential, orally administrated, anticancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Citidina Monofosfato/análogos & derivados , Glioblastoma/tratamiento farmacológico , Nucleótidos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citidina Monofosfato/química , Citidina Monofosfato/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/patología , Humanos , Estructura Molecular , Nucleótidos/síntesis química , Nucleótidos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Several ribonucleoside analogues with modifications in the nucleobase and sugar moiety have been screened for anti-glioma activity in the T98G glioma cell line using cervical (HeLa) cell line as reference human malignant cells, and lung fibroblast (MCR-5) cell line as non-cancerous reference cells. Among the investigated compounds, ribonucleosides containing 6-chloropurine (3), 7-guanine (5) and a pyrrolopyrimidine (18) as nucleobases, show promising anti-glioma activity with good selectivity indices, and can be considered as lead structures for further anti-cancer studies.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Antineoplásicos/farmacología , Citidina/análogos & derivados , Citidina/farmacología , Guanosina/análogos & derivados , Guanosina/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Furanos/farmacología , Glioblastoma/tratamiento farmacológico , Células HeLa , Humanos , Concentración 50 InhibidoraRESUMEN
New aromatic and aliphatic 3'-O-acyl-5-fluoro-2'-deoxyuridine derivatives were synthesized and evaluated as candidates for prodrugs against various cancer cell lines. As the most promising candidate for antimalignant therapeutics was found a dual-acting acyl derivative 7h, which apparently released not only the known anticancer nucleoside, 5-fluoro-2'-deoxyuridine (FdU), but also an additional active metabolite, acetylsalicylic acid, reinforcing thus therapeutic effect of FdU. Promising therapeutic indices showed also some aromatic dicarboxylic acids derivatives decorated with FdU esters (11 and 12).
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Desoxiuridina/análogos & derivados , Profármacos/farmacología , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Desoxiuridina/síntesis química , Desoxiuridina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Relación Estructura-ActividadRESUMEN
Fragile histidine triad (HIT) proteins (Fhits) occur in all eukaryotes but their function is largely unknown. Human Fhit is presumed to function as a tumour suppressor. Previously, we demonstrated that Fhits catalyse hydrolysis of not only dinucleoside triphosphates but also natural adenosine 5'-phosphoramidate (NH2-pA) and adenosine 5'-phosphosulfate (SO4-pA) as well as synthetic adenosine 5'-phosphorofluoridate (F-pA). In the present study, we describe an Fhit-catalysed displacement of the amino group of nucleoside 5'-phosphoramidates (NH2-pNs) or the sulfate moiety of nucleoside 5'-phosphosulfates (SO4-pNs) by fluoride anion. This results in transient accumulation of the corresponding nucleoside 5'-phosphorofluoridates (F-pNs). Substrate specificity and kinetic characterization of the fluorolytic reactions catalysed by the human Fhit and other examples of involvement of fluoride in the biochemistry of nucleotides are described. Among other HIT proteins, human histidine triad nucleotide-binding protein (Hint1) catalysed fluorolysis of NH2-pA 20 times and human Hint2 40 times more slowly than human Fhit.
Asunto(s)
Ácido Anhídrido Hidrolasas/metabolismo , Adenosina Monofosfato/análogos & derivados , Adenosina Fosfosulfato/metabolismo , Fluoruros/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfatos/metabolismo , Adenosina Monofosfato/metabolismo , Catálisis , Humanos , Cinética , Estructura Molecular , Especificidad por SustratoRESUMEN
A variety of 4'-aryl-3-(arylmethylidene)-1â³-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3â³-[3H]indole]-2,2â³(1â³H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 "liver", HELA "cervical" and PC3 "prostate" cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r2=0.903-0.812, r2adjusted=0.855-0.672, r2prediction=0.773-0.605).
Asunto(s)
Antineoplásicos , Diseño de Fármacos , Indoles , Relación Estructura-Actividad Cuantitativa , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Doxorrubicina/química , Doxorrubicina/farmacología , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4'-aryl-5'a,6'-dihydro-1'-methyl-spiro[3H-indole-3,2'(1'H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones 4a-o in good yields. Compound 4l exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC(50) = 12.16 µM) compared to that of Doxorubicin (IC(50) = 7.36 µM), and the other synthesized compounds revealed moderate anti-tumor properties against HCT116 (colon), MCF7 (breast) and HEPG2 (liver) human tumor cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements controlling the observed anti-tumor properties. It was found that the major structural factors affecting potency of these compounds were related to their basic skeleton.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Pirroles/química , Relación Estructura-Actividad Cuantitativa , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Reproducibilidad de los Resultados , Compuestos de Espiro/síntesis químicaRESUMEN
Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5'-monophosphates, and their efficiency correlated well with the pK(a) values of the aryloxy groups present.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Nucleósidos/síntesis química , Nucleótidos/síntesis química , Organofosfonatos/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Línea Celular , Células Cultivadas , VIH/fisiología , Humanos , Hidroxiácidos/síntesis química , Hidroxiácidos/química , Hidroxiácidos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nucleósidos/química , Nucleósidos/farmacología , Nucleótidos/química , Nucleótidos/farmacología , Organofosfonatos/química , Organofosfonatos/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
A configuration of ligands around a phosphorus atom in P-chiral dinucleoside monophosphate analogues can be described using DP/LP stereochemical notation, which allows immediate correlation between the notation of configuration and the actual spatial arrangement of the phosphorus ligands. The area of applications of this new stereochemical nomenclature covers dinucleoside units bridged by virtually any type of tri-and tetra-coordinated phosphorus moieties, that is, phosphorothioates, phosphoramidates, phosphoramidites, boranephosphates, methanephosphonates, H-phosphonates, and many others.
Asunto(s)
Química/métodos , Fosfatos de Dinucleósidos/química , Nucleósidos/química , Nucleótidos/química , Terminología como Asunto , Ligandos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Oxígeno/química , Proteínas Recombinantes de Fusión/química , EstereoisomerismoRESUMEN
Aryl nucleoside 5'-H-phosphonates 4 bearing AZT or 2',3'-dideoxyuridine moieties were subjected to reaction with various aromatic aldehydes to produce nucleoside 5'-alpha-hydroxyphosphonate derivatives 2 as potential anti-HIV agents. Stability of the title compounds in cell culture media was investigated and three distinct decomposition pathways were identified. The anti-HIV activity of hydroxyphosphonates 2 correlates well with the type and extent of their chemical or enzymatic degradation in culture medium (RPMI 1640 containing 10% FBS), suggesting that aryl nucleoside 5'-hydroxyphosphonates 2 act as depot forms of the parent antiviral nucleosides.
Asunto(s)
Fármacos Anti-VIH/síntesis química , VIH/efectos de los fármacos , Hidroxiácidos/química , Hidroxiácidos/farmacología , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Fármacos Anti-VIH/farmacología , Línea Celular , Células Cultivadas , Humanos , Hidroxiácidos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Replicación Viral/efectos de los fármacos , Zidovudina/química , Zidovudina/farmacologíaRESUMEN
Sixteen diribonucleoside (3'-5')-H-phosphonates were synthesized via condensation of the protected ribonucleoside 3'-H-phosphonates with nucleosides, and the influence of a nucleoside sequence on the observed stereoselectivity was analyzed. 31P NMR spectroscopy was used to evaluate a relationship between chemical shift and absolute configuration at the phosphorous center of the H-phosphonate diesters as well as of the corresponding phosphorothioate diesters. Although for the most cases such correlation was found, there was however several exceptions to the rule where the relative positions of resonances arisingfrom Rp and Sp diastereomers were reversed.
Asunto(s)
Fosfatos de Dinucleósidos/síntesis química , Compuestos Organofosforados/química , Fosfatos de Dinucleósidos/química , Espectroscopía de Resonancia Magnética , Isótopos de Fósforo/química , EstereoisomerismoRESUMEN
Chemoselectivity and stereospecificity of iodine mediated oxidative couplings using separate diastereomers of dinucleoside H-phosphonate and H-phosphonothioate with various N- and O-binucleophiles were investigated.
Asunto(s)
Fosfatos de Dinucleósidos/química , Organofosfonatos , Ésteres , Indicadores y Reactivos , EstereoisomerismoRESUMEN
An efficient and stereospecific synthesis of dinucleoside 4'-(2,2':6',2''-terpyridyl)phosphonate 2 and 5-(2,2'-bipyridyl)phosphonate 3 via a palladium(0) cross coupling strategy has been developed.