RESUMO
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.
RESUMO
We have designed a new type of AZT and ddU phosphoramidate diesters containing various combinations of 2-, 3-, 4-aminopyridine and 2-, 3-, 4-hydroxypyridine moieties attached to the phosphorus center, as potential anti-HIV pronucleotides. Depending on the pKa values of the aminopyridines and the hydroxypyridines used, alternative synthetic strategies based on H-phosphonate chemistry were developed for their preparation. Synthetic aspects of these transformations and the biological activity of the synthesized compounds are discussed.
Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/química , Desenho de Fármacos , Organofosfonatos/uso terapêutico , Ácidos Fosfóricos/farmacologia , Amidas/síntese química , Amidas/química , Aminopiridinas , Fármacos Anti-HIV/síntese química , Didesoxinucleosídeos , Organofosfonatos/química , Ácidos Fosfóricos/síntese química , Ácidos Fosfóricos/química , Piridinas , ZidovudinaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Monofosfato de Citidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Nucleotídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Monofosfato de Citidina/química , Monofosfato de Citidina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Humanos , Estrutura Molecular , Nucleotídeos/síntese química , Nucleotídeos/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Adenosina/análogos & derivados , Adenosina/farmacologia , Antineoplásicos/farmacologia , Citidina/análogos & derivados , Citidina/farmacologia , Guanosina/análogos & derivados , Guanosina/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/farmacologia , Glioblastoma/tratamento farmacológico , Células HeLa , Humanos , Concentração Inibidora 50RESUMO
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).
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desoxiuridina/análogos & derivados , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Desoxiuridina/síntese química , Desoxiuridina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-AtividadeRESUMO
Recently, AZT (N-pyridyl)phosphoramidates were reported as a new type of potential anti-HIV therapeutics. In continuation of that work, here we present new (N-heteroaryl)phosphoramidate derivatives of antiviral 2',3'-dideoxynucleosides containing other types of N-heteroaryl moieties, particularly those with higher lipophilicity. The present studies comprise mechanistic investigations using (31)P NMR correlation analysis, which permitted improvements in the synthetic procedures. The obtained compounds were tested in biological systems to establish their cytotoxicity and anti-HIV activity. The results were analyzed with respect to possible correlations between biological and physico-chemical properties of the phosphoramidates studied, to get some insight into their antiviral mode of action.
Assuntos
Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular , Didesoxinucleosídeos/síntese química , Didesoxinucleosídeos/química , Relação Dose-Resposta a Droga , HIV-1/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Hidrolases Anidrido Ácido/metabolismo , Monofosfato de Adenosina/análogos & derivados , Adenosina Fosfossulfato/metabolismo , Fluoretos/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfatos/metabolismo , Monofosfato de Adenosina/metabolismo , Catálise , Humanos , Cinética , Estrutura Molecular , Especificidade por SubstratoRESUMO
This chapter provides an overview of recent advances in the development of new methods and protocols for the formation of the P-C bond using H-phosphonate diesters as starting materials. Various chemical and stereochemical aspects of the transition metal-catalyzed cross-coupling and organocatalyst-promoted reactions which are relevant to the synthesis of structurally diverse C-phosphonate derivatives are surveyed.
RESUMO
This review covers recent progress in the preparation of H-phosphonate mono- and diesters, basic studies on mechanistic and stereochemical aspects of this class of phosphorus compounds, and their fundamental chemistry in terms of transformation of P-H bonds into P-heteroatom bonds. Selected recent applications of H-phosphonate derivatives in basic organic phosphorus chemistry and in the synthesis of biologically important phosphorus compounds are also discussed.
Assuntos
Organofosfonatos/síntese química , Fósforo/química , Ésteres , Nucleosídeos/química , Oligonucleotídeos/química , Compostos Organofosforados/química , EstereoisomerismoRESUMO
Nucleotides, their analogues, and other phosphate esters and phosphoramidates often contain the triethylammonium cation as a counterion. We found that this may be lost during chromatographic purification or concentration of solutions, yielding products in acidic forms or containing sub-stoichiometric amounts of the counterion. This in turn may be detrimental, e.g., due to possible decomposition of a compound or inaccurate sample preparation. Correlations between the structure of studied compounds and their susceptibility for cation loss were analyzed. Modifications in preparative techniques were developed to obtain the studied compounds with stoichiometric anion to cation ratios.
Assuntos
Nucleotídeos/análise , Compostos de Amônio Quaternário/químicaRESUMO
Nucleoside H-phosphonates activated with a condensing agent spontaneously formed nucleoside 3',5'-cyclic H-phosphonates. The cyclization was stereoselective and produced one of the P-diastereomers in preponderance (de ca. 80%). Nucleoside 3',5'-cyclic H-phosphonates were stereochemically unstable and underwent epimerization affording the thermodynamically more stable diastereomer as a major product (de ca. 80%). They were susceptible to hydrolysis, transesterification, and oxidation and by changing oxidation protocols nucleoside 3',5'-cyclic phosphate analogues, e.g. phosphodiesters, phosphorothioate diesters, and phosphotriesters, were obtained.
Assuntos
Nucleosídeos/síntese química , Nucleotídeos/síntese química , Compostos Organotiofosforados/química , Ciclização , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nucleosídeos/química , Nucleotídeos/química , Organofosfonatos , OxirreduçãoRESUMO
New synthetic protocol for the preparation of nucleoside 5'-(N-aryl)phosphoramidate monoesters 4 was developed. It consisted of a condensation of the corresponding nucleoside 5'-H-phosphonates with aromatic- or heteroaromatic amines promoted by diphenyl phosphorochloridate, followed by oxidation of the produced H-phosphonamidates with iodine/water. 5'-(N-Aryl)phosphoramidate monoesters derived from 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyuridine (ddU) nucleosides and various aromatic and heteroaromatic amines were evaluated as potential anti-HIV drugs. It was found that these compounds act most likely as pronucleotides and that some of them have therapeutic indices superior to those of the reference AZT.
Assuntos
Fármacos Anti-HIV/síntese química , Organofosfonatos/síntese química , Nucleosídeos de Pirimidina/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células Cultivadas , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Organofosfonatos/química , Organofosfonatos/farmacologia , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Efficiency and stereoselectivity of condensations of ribonucleoside 3'-H-phosphonates with ethanol promoted by pivaloyl chloride were investigated as a function of tertiary amines used. Side reactions leading to an increased demand for the condensing agent were identified as derived from an attack of the pivalate anion at carbonyl centers of reactive pivaloyl derivatives. The conditions that secured quantitative yields of H-phosphonate diester condensations were assessed. Several tertiary amines promoted condensations with stereoselectivity higher than that observed for pyridine derivatives. A correlation between diastereoselectivity of the product formation and Brønsted and H-bonding basicities of the amine used was found.
Assuntos
Modelos Químicos , Organofosfonatos/química , Ribonucleotídeos/química , Ésteres/síntese química , Ésteres/química , Etanol/química , Ligação de Hidrogênio , Estrutura Molecular , Ácidos Pentanoicos/química , EstereoisomerismoRESUMO
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.
Assuntos
Fármacos Anti-HIV/síntese química , Nucleosídeos/síntese química , Nucleotídeos/síntese química , Organofosfonatos/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Células Cultivadas , HIV/fisiologia , Humanos , Hidroxiácidos/síntese química , Hidroxiácidos/química , Hidroxiácidos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/farmacologia , Nucleotídeos/química , Nucleotídeos/farmacologia , Organofosfonatos/química , Organofosfonatos/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Recently, we have proposed a new D(P)/L(P) stereochemical notation for P-chiral dinucleoside monophosphate analogues based on a structural relationship between compounds. As an extension of this work, we present here applications of the D(P)/L(P) notation for tracking stereochemistry of reaction pathways involving H-phosphonate, phosphoramidite, phosphorotriester, and other intermediates frequently met in the nucleotide chemistry.
Assuntos
Nucleosídeos/química , Nucleotídeos/química , Terminologia como Assunto , Fenômenos Bioquímicos , Estrutura Molecular , EstereoisomerismoRESUMO
The D(P)/L(P) convention is a stereochemical notation for P-chiral nucleotide analogs and related compounds. In contrast to the absolute R(P)/S(P) notation, the D(P)/L(P) system is based on a geometrical relationship between substituents in a dinucleoside monophosphate skeleton. The D(P)/L(P) notation is a convenient alternative to the R(P)/S(P) notation for stereochemical correlation analysis of physical, chemical, and biological properties of nucleotide and oligonucleotide analogs bearing any type of tri- or tetra-coordinated phosphorus moiety.
Assuntos
Nucleotídeos/química , Ligantes , EstereoisomerismoRESUMO
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.
Assuntos
Química/métodos , Fosfatos de Dinucleosídeos/química , Nucleosídeos/química , Nucleotídeos/química , Terminologia como Assunto , Ligantes , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Oxigênio/química , Proteínas Recombinantes de Fusão/química , EstereoisomerismoRESUMO
Recently, we have proposed a new DP/LP stereochemical notation for P-chiral dinucleoside monophosphate analogues that permits simple correlation between spatial arrangement of the substituents and the configuration at the phosphorus center. As an extension of this work, we present here applications of the DP/LP notation to derivatives containing only one nucleoside unit (e.g., alkyl nucleoside phosphodiesters, nucleoside phosphomonoesters, cyclic phosphate derivatives, nucleoside di-, and triphosphates) and to nonnucleosidic phosphorus compounds.
Assuntos
Bioquímica/métodos , Nucleosídeos/química , Nucleotídeos/química , Fósforo/química , Terminologia como Assunto , Ligantes , Modelos Químicos , Estrutura Molecular , EstereoisomerismoRESUMO
The crystal structures of triethylammonium adenosine cyclic 2',3'-phosphate {systematic name: triethylammonium 4-(6-aminopurin-9-yl)-6-hydroxymethyl-2-oxido-2-oxoperhydrofurano[3,4-c][1,3,2]dioxaphosphole}, Et(3)NH(2',3'-cAMP) or C(6)H(16)N(+).C(10)H(11)N(5)O(6)P(-), (I), and guanosine cyclic 2',3'-phosphate monohydrate {systematic name: triethylammonium 6-hydroxymethyl-2-oxido-2-oxo-4-(6-oxo-1,6-dihydropurin-9-yl)perhydrofurano[3,4-c][1,3,2]dioxaphosphole monohydrate}, [Et(3)NH(2',3'-cGMP)].H(2)O or C(6)H(16)N(+).C(10)H(11)N(5)O(7)P(-).H(2)O, (II), reveal different nucleobase orientations, viz. anti in (I) and syn in (II). These are stabilized by different inter- and intramolecular hydrogen bonds. The structures also exhibit different ribose ring puckering [(4)E in (I) and (3)T(2) in (II)] and slightly different 1,3,2-dioxaphospholane ring conformations, viz. envelope in (I) and puckered in (II). Infinite ribbons of 2',3'-cAMP(-) and helical chains of 2',3'-cGMP(-) ions, both formed by O-H...O, N-H...X and C-H...X (X = O or N) hydrogen-bond contacts, characterize (I) and (II), respectively.
Assuntos
AMP Cíclico/química , GMP Cíclico/química , AMP Cíclico/análogos & derivados , GMP Cíclico/análogos & derivados , Conformação MolecularRESUMO
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.