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1.
Bioorg Chem ; 117: 105419, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34689082

RESUMEN

A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC50 value in B16 cells was almost 9-fold better than that of ibrutinib. Mechanism of action studies showed that YL7 inhibited proliferation and migration and induced G1 cell cycle arrest, apoptosis and autophagy in B16 cells. Further assessment of in vivo antitumor efficacies demonstrated that YL7 significantly inhibited the growth of B16 melanoma. These preliminary studies suggest that it is reasonable to modify the structure of ibrutinib for antimelanoma treatment.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/farmacología , Descubrimiento de Drogas , Melanoma/tratamiento farmacológico , Piperidinas/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Melanoma/patología , Ratones , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Neoplasias Cutáneas/patología , Relación Estructura-Actividad , Melanoma Cutáneo Maligno
2.
Eur J Med Chem ; 225: 113811, 2021 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-34507011

RESUMEN

A DNA intercalating agent Amonafide interferes with topoisomerase 2 (Topo II) activity and prevents re-ligation of DNA strands, leading to double strand breaks (DSB). If DSB repair fails, cells stop dividing and eventually die. In a search of approaches to enhance anti-cancer activities of Topo II inhibitors, we hypothesized that introduction of additional damage in proximity to the DSB may suppress DNA repair and enhance cancer cell killing. Accordingly, chimeric molecules were created that target a DNA alkylating component to the proximity of Topo II-induced DSBs. These chimeras consist of Amonafide or its 4-amino isomer, and DNA methylating methyl triazene moiety Azene protected with a carbamate group, connected via linker. Treatment of cancer cells with the chimeric molecules leads to significantly higher number of DSBs, which were repaired slower compared to Amonafide or monomethyl triazene-treated cells. On the other hand, methyl triazene linked to non-intercalating Amonafide analogs was ineffective. Together, these data strongly support our hypothesis. In line with increased DSBs, the chimeric molecules exhibited significantly higher antiproliferative activity in cancer cell lines compared to Amonafide or monomethyl triazene constituent Azene. We utilized the fluorescent properties of chimera Amonafidazene to develop ''photo-switchable'' reporting system to monitor the prodrug activation. Using this approach, we found that the chimera accumulated and was activated at the tumor sites specifically and demonstrated significantly stronger tumor suppressing activities compared to Amonafide in a xenograft model. Therefore, targeting alkylating groups to the proximity of DSB sites may become an effective approach towards enhancing anti-cancer activities of inhibitors of topoisomerases.


Asunto(s)
Adenina/farmacología , Antineoplásicos/farmacología , ADN de Neoplasias/efectos de los fármacos , Organofosfonatos/farmacología , Adenina/síntesis química , Adenina/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Metilación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Organofosfonatos/síntesis química , Organofosfonatos/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
3.
ChemMedChem ; 16(10): 1605-1608, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-33559353

RESUMEN

A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non-small-cell lung cancers. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA-driven matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found to be active on RET in a biochemical assay, but reduced cell viability in non-RET-driven cell lines (EC50 =1 and 3 µM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8 p, which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC50 =5.92 µM, LC-2/ad EC50 =0.016 µM, RET IC50 =0.000326 µM).


Asunto(s)
Adenina/farmacología , Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/farmacología , Adenina/síntesis química , Adenina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-ret/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
4.
RNA ; 27(2): 151-162, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33177187

RESUMEN

A key approach for improving siRNA efficacy is chemical modifications. Through an in silico screening of modifications at the 5'-end nucleobase of the guide strand, an adenine-derived compound called 6-(3-(2-carboxyethyl)phenyl)-purine (6-mCEPh-purine) was identified to improve the RNAi activity in cultured human cells and in vivo mouse models. Nevertheless, it remains unclear how this chemical modification enhances the siRNA potency. Here, we used a series of biochemical approaches to quantitatively evaluate the effect of the 6-mCEPh-purine modification at each step in the assembly of the RNAi effector complex called RISC. We found that the modification improves the formation of mature RISC at least in two different ways, by fixing the loading orientation of siRNA duplexes and increasing the stability of mature RISC after passenger strand ejection. Our data will provide a molecular platform for further development of chemically modified siRNA drugs.


Asunto(s)
Adenina/farmacología , Proteínas Argonautas/genética , Interferencia de ARN/efectos de los fármacos , ARN Bicatenario/genética , ARN Interferente Pequeño/agonistas , Complejo Silenciador Inducido por ARN/agonistas , Adenina/análogos & derivados , Adenina/síntesis química , Proteínas Argonautas/metabolismo , Emparejamiento Base , Secuencia de Bases , Células HEK293 , Humanos , Metilación , Unión Proteica , ARN Bicatenario/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Complejo Silenciador Inducido por ARN/genética , Complejo Silenciador Inducido por ARN/metabolismo
5.
RNA ; 27(2): 163-173, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33177188

RESUMEN

Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.


Asunto(s)
Adenina/farmacología , Proteínas Argonautas/genética , Interferencia de ARN/efectos de los fármacos , ARN Bicatenario/genética , ARN Interferente Pequeño/agonistas , Complejo Silenciador Inducido por ARN/agonistas , Adenina/análogos & derivados , Adenina/síntesis química , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Animales , Apolipoproteína B-100/antagonistas & inhibidores , Apolipoproteína B-100/sangre , Apolipoproteína B-100/química , Apolipoproteína B-100/genética , Proteínas Argonautas/metabolismo , Emparejamiento Base , Secuencia de Bases , Sitios de Unión , Colesterol/sangre , Células HeLa , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Metilación , Ratones , Ratones Noqueados , Modelos Moleculares , Unión Proteica , ARN Bicatenario/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Complejo Silenciador Inducido por ARN/genética , Complejo Silenciador Inducido por ARN/metabolismo , Uridina Monofosfato/química , Uridina Monofosfato/metabolismo
6.
J Mater Chem B ; 8(48): 11044-11054, 2020 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-33196727

RESUMEN

The ability of the multidentate nucleobases, adenine and thymine, to coordinate polyoxometalate and metal ions leading to the formation of self-assembled nanostructures and their strong cytotoxicity toward cancer cell lines have been demonstrated. A unique synthetic approach is developed to make a series of functional nanoscale hybrid materials consisting of nucleobases (adenine and thymine) and phosphomolybdic acid (PMA) through solid state chemical reaction and self-assembly process. Adenine was protonated through its ring nitrogen, while the ketone group in thymine was protonated during the addition of PMA to these nucleobases. The self-assembled nanostructures formed as a result of the electrostatic interaction between the protonated nucleobases and polyanionic PMA. To promote the base pairing between the nucleobases, chloroaurate ions and silver ions were added to each PMA/adenine and PMA/thymine nanostructures. The complexation between the nucleobases and the added metal ions was found to drive the formation of subsequent self-assembled nanostructures. All the materials were screened for their anticancer activity against breast (MDAMB-231) and prostate (PC-3) cancer cells, and non-cancerous keratinocyte cells HaCaT. PMA/adenine/[AuCl4]- and PMA/thymine/Ag+ nanostructures were found to have strong anti-cancer activity, while PMA/adenine/Ag+, PMA/thymine/[AuCl4]-, and PMA/pdenine, PMA/thymine nanostructures did not exhibit such activity. The unique redox properties of these materials and the self-assembly of the PMA and metal ions were the major factors responsible for the cytotoxicity. This unique approach of making functional nanomaterials incorporate the nucleobase, PMA and metal ions using solid state self-assembly and their anti-cancer applications are considered to be an effective approach for the development of inorganic nucleoside analogue bio-pharmaceutical agents.


Asunto(s)
Adenina/síntesis química , Citotoxinas/síntesis química , Metales Pesados/síntesis química , Nanoestructuras/química , Ácidos Fosfóricos/síntesis química , Timina/síntesis química , Adenina/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citotoxinas/toxicidad , Humanos , Metales Pesados/toxicidad , Molibdeno/toxicidad , Nanoestructuras/toxicidad , Ácidos Fosfóricos/toxicidad , Timina/toxicidad
7.
Molecules ; 25(21)2020 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-33105870

RESUMEN

Nicotinamide adenine dinucleotide (NAD) kinases are essential and ubiquitous enzymes involved in the tight regulation of NAD/nicotinamide adenine dinucleotide phosphate (NADP) levels in many metabolic pathways. Consequently, they represent promising therapeutic targets in cancer and antibacterial treatments. We previously reported diadenosine derivatives as NAD kinase inhibitors with bactericidal activities on Staphylococcus aureus. Among them, one compound (namely NKI1) was found effective in vivo in a mouse infection model. With the aim to gain detailed knowledge about the selectivity and mechanism of action of this lead compound, we planned to develop a chemical probe that could be used in affinity-based chemoproteomic approaches. Here, we describe the first functionalized chemical probe targeting a bacterial NAD kinase. Aminoalkyl functional groups were introduced on NKI1 for further covalent coupling to an activated SepharoseTM matrix. Inhibitory properties of functionalized NKI1 derivatives together with X-ray characterization of their complexes with the NAD kinase led to identify candidate compounds that are amenable to covalent coupling to a matrix.


Asunto(s)
Adenina/análogos & derivados , Adenosina/síntesis química , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Adenina/síntesis química , Adenina/farmacología , Adenosina/farmacología , Secuencia de Aminoácidos , Animales , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Ratones , Modelos Moleculares , NADP/química , Conformación Proteica , Sefarosa/química , Staphylococcus aureus
8.
Org Lett ; 22(15): 5726-5730, 2020 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-32525688

RESUMEN

Aspongdopamines A and B (1 and 2), unusual adducts composed of N-acetyldopamine and adenine were isolated from the insect Aspongopus chinensis. Compounds 1 and 2 are positional isomers both isolated as racemates. Chiral separation assisted by 14-step total synthesis and computation including vibrational circular dichroism calculations allowed us to unambiguously assign the absolute configurations of eight stereoisomers. Renal fibrosis inhibition of the stereoisomers was evaluated in TGF-ß1-induced rat kidney epithelial cells.


Asunto(s)
Adenina/síntesis química , Productos Biológicos/farmacología , Dopamina/análogos & derivados , Insectos/efectos de los fármacos , Factor de Crecimiento Transformador beta1/química , Adenina/química , Animales , Dicroismo Circular , Dopamina/síntesis química , Dopamina/química , Estructura Molecular , Ratas , Estereoisomerismo , Factor de Crecimiento Transformador beta1/metabolismo
9.
J Inorg Biochem ; 203: 110879, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31683127

RESUMEN

The reaction of adenine with 2-chloropyrimidine yields as a major product the unexpected N7-(2-pyrimidyl)-adenine (1) and as a minor one N9-(2-pyrimidyl)-adenine (2). Both compounds have been characterized by X-ray diffraction analysis. Moreover, we report the formation of a 1:1 co-crystal (3) composed by compound (1) and adenine that was formed serendipitously during the synthesis of (1). Unexpectedly, the treatment of (1) with Brönsted acids like HCl or HNO3 causes the opening of the imidazole ring of the N7-substituted adenine, yielding N5-(pyrimidin-2-yl)pyrimidine-4,5,6-triamine (4-7) which we have X-ray characterized in its neutral, (4), monoprotonated [nitrate salt (6)] and diprotonated forms [hydrochloride salt (5) and, also, a tetrachlorozincate salt (7)]. Finally, we have used compound (5) as ligand to synthesize and X-ray characterize its complexes with Ir(III) and Ag(I) (compounds (8) and (9), respectively), where the latter is a 2D coordination polymer and the former is a discrete mononuclear complex. We have studied the supramolecular assemblies formed in the solid state by using density functional theory (DFT) calculations. Finally, DNA-docking studies of several compounds have been carried out in order to analyze their ability to interact with the DNA.


Asunto(s)
Adenina/análogos & derivados , Pirimidinas/química , Adenina/síntesis química , Adenina/metabolismo , Animales , Sitios de Unión , Bovinos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Cristalografía por Rayos X , ADN/química , ADN/metabolismo , Teoría Funcional de la Densidad , Modelos Químicos , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/metabolismo
10.
Org Biomol Chem ; 17(46): 9913-9923, 2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31720670

RESUMEN

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 7-10. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 7-10, adenine-(methoxy)ethoxy-Pα,α-dithio-triphosphate, 8, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 8 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 8 did not activate P2Y1,2,6 receptors. Analog 8 was not toxic to cultured chondrocytes at 100 µM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.


Asunto(s)
Adenina/farmacología , Pirofosfato de Calcio/antagonistas & inhibidores , Condrocitos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Osteoartritis de la Rodilla/tratamiento farmacológico , Polifosfatos/farmacología , Pirofosfatasas/antagonistas & inhibidores , Compuestos de Sulfhidrilo/farmacología , Adenina/síntesis química , Adenina/química , Pirofosfato de Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Hidrolasas Diéster Fosfóricas/metabolismo , Polifosfatos/química , Pirofosfatasas/metabolismo , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/química
11.
Nat Commun ; 10(1): 4413, 2019 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-31562325

RESUMEN

The synthesis of nucleobases in natural environments, especially in interstellar molecular clouds, is the focus of a long-standing debate regarding prebiotic chemical evolution. Here we report the simultaneous detection of all three pyrimidine (cytosine, uracil and thymine) and three purine nucleobases (adenine, xanthine and hypoxanthine) in interstellar ice analogues composed of simple molecules including H2O, CO, NH3 and CH3OH after exposure to ultraviolet photons followed by thermal processes, that is, in conditions that simulate the chemical processes accompanying star formation from molecular clouds. Photolysis of primitive gas molecules at 10 K might be one of the key steps in the production of nucleobases. The present results strongly suggest that the evolution from molecular clouds to stars and planets provides a suitable environment for nucleobase synthesis in space.


Asunto(s)
Adenina/química , Citosina/química , Hipoxantina/química , Timina/química , Uracilo/química , Xantina/química , Adenina/síntesis química , Amoníaco/química , Monóxido de Carbono/química , Citosina/síntesis química , Evolución Química , Medio Ambiente Extraterrestre , Hipoxantina/síntesis química , Hielo , Metanol/química , Estructura Molecular , Procesos Fotoquímicos/efectos de la radiación , Timina/síntesis química , Rayos Ultravioleta , Uracilo/síntesis química , Agua/química , Xantina/síntesis química
12.
Bioorg Med Chem ; 27(8): 1704-1713, 2019 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-30879860

RESUMEN

Synthetic derivatives of cyclic adenosine monophosphate, such as halogenated or other more hydrophobic analogs, are widely used compounds, to investigate diverse signal transduction pathways of eukaryotic cells. This inspired us to develop cyclic nucleotides, which exhibit chemical structures composed of brominated 7-deazaadenines and the phosphorylated ribosugar. The synthesized 8-bromo- and 7-bromo-7-deazaadenosine-3',5'-cyclic monophosphates rank among the most potent activators of cyclic nucleotide-regulated ion channels as well as cAMP-dependent protein kinase. Moreover, these substances bind tightly to exchange proteins directly activated by cAMP.


Asunto(s)
AMP Cíclico/análogos & derivados , AMP Cíclico/farmacología , Adenina/análogos & derivados , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Animales , AMP Cíclico/síntesis química , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/agonistas , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Activación Enzimática/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido/agonistas , Factores de Intercambio de Guanina Nucleótido/metabolismo , Halogenación , Humanos , Ratones
13.
J Med Chem ; 62(4): 1989-1998, 2019 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-30707835

RESUMEN

Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 that showed stronger period effects (0.32 µM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that NCC007 inhibited CKIα and CKIδ with an IC50 of 1.8 and 3.6 µM. We further demonstrated that NCC007 lengthened the period of mouse behavioral rhythms in vivo. Thus, NCC007 is a valuable tool compound to control circadian rhythms through CKI inhibition.


Asunto(s)
Adenina/análogos & derivados , Caseína Quinasa Ialfa/antagonistas & inhibidores , Ritmo Circadiano/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Adenina/síntesis química , Adenina/metabolismo , Adenina/farmacología , Animales , Sitios de Unión , Caseína Quinasa Ialfa/química , Caseína Quinasa Ialfa/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Unión Proteica
14.
Nucleic Acids Res ; 47(3): 1268-1277, 2019 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-30517733

RESUMEN

In addition to DNA cytosine methylation (5-methyl-2'-deoxycytidine, m5dC), DNA adenine methylation (N6-methyl-2'-deoxyadenosine, m6dA) is another DNA modification that has been discovered in eukaryotes. Recent studies demonstrated that the content and distribution of m6dA in genomic DNA of vertebrates and mammals exhibit dynamic regulation, indicating m6dA may function as a potential epigenetic mark in DNA of eukaryotes besides m5dC. Whether m6dA undergoes the further oxidation in a similar way to m5dC remains elusive. Here, we reported the existence of a new DNA modification, N6-hydroxymethyl-2'-deoxyadenosine (hm6dA), in genomic DNA of mammalian cells and tissues. We found that hm6dA can be formed from the hydroxylation of m6dA by the Fe2+- and 2-oxoglutarate-dependent ALKBH1 protein in genomic DNA of mammals. In addition, the content of hm6dA exhibited significant increase in lung carcinoma tissues. The increased expression of ALKBH1 in lung carcinoma tissues may contribute to the increase of hm6dA in DNA. Taken together, our study reported the existence and formation of hm6dA in genomic DNA of mammals.


Asunto(s)
Adenina/metabolismo , Metilación de ADN/genética , ADN/genética , Epigénesis Genética , Adenina/análogos & derivados , Adenina/síntesis química , Adenina/farmacología , Animales , ADN/efectos de los fármacos , ADN/metabolismo , Genoma/efectos de los fármacos , Células HeLa , Humanos , Hidroxilación/efectos de los fármacos , Mamíferos
15.
Artículo en Inglés | MEDLINE | ID: mdl-30188772

RESUMEN

A synthesis of cyclobutene nucleoside analogs in which the nucleobase is tethered by a methylene group is described. The coupling of 6-chloropurine with 3-hydroxymethyl-cyclobutanone proceeds via its triflate to give both N-7 and N-9 regioisomers with relative yields corresponding to the calculated charge distribution of the 6-chloropurinyl anion. The stereoselective reduction of the N-alkylated ketones yielded quantitatively one stereoisomer in each case. The structural assignments were based on spectroscopic data and single crystal X-ray diffraction. Attempts to photoexcite the N-7 and N-9 ketones in order to promote ring-expansion did not ensue. Preliminary evidence suggests a photodecarbonylation to cyclopropanes took place.


Asunto(s)
Ciclobutanos/síntesis química , Adenina/análogos & derivados , Adenina/síntesis química , Adenina/química , Ciclobutanos/química , Nucleósidos/síntesis química , Nucleósidos/química , Purinas/química , Estereoisomerismo
16.
ChemMedChem ; 13(17): 1779-1796, 2018 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-29968968

RESUMEN

A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 µm in HEK293 cell-based assays.


Asunto(s)
Adenina/análogos & derivados , Adenilil Ciclasas/metabolismo , Bacillus anthracis/enzimología , Bordetella pertussis/enzimología , Inhibidores Enzimáticos/farmacología , Organofosfonatos/farmacología , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Organofosfonatos/síntesis química , Organofosfonatos/química , Relación Estructura-Actividad
17.
Chemistry ; 24(46): 11890-11894, 2018 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-29790604

RESUMEN

(3,4-Dihydroxybut-1-ynyl)uracil, -cytosine and -7-deazaadenine 2'-deoxyribonucleoside triphosphates (dNTPs) were prepared by direct aqueous Sonogashira cross-coupling of halogenated dNTPs with dihydroxybut-1-yne and converted to 3,4-dihydroxybutyl dNTPs through catalytic hydrogenation. Sodium periodate oxidative cleavage of dihydroxybutyl-dUTP gave the desired aliphatic aldehyde-linked dUTP, whereas the oxidative cleavage of the corresponding deazaadenine dNTP gave a cyclic aminal. All dihydroxyalkyl or -alkynyl dNTPs and the formylethyl-dUTP were good substrates for DNA polymerases and were used for synthesis of diol- or aldehyde-linked DNA. The aldehyde linked DNA was used for the labelling or bioconjugations through hydrazone formation or reductive aminations.


Asunto(s)
Adenina/análogos & derivados , Aldehídos/química , Citosina/química , ADN Polimerasa Dirigida por ADN/metabolismo , ADN/metabolismo , Nucleótidos de Desoxiuracil/síntesis química , Uracilo/metabolismo , Adenina/síntesis química , Adenina/química , Aminación , ADN/química , ADN Polimerasa Dirigida por ADN/química , Nucleótidos de Desoxiuracil/química , Estructura Molecular , Nucleótidos , Uracilo/química
18.
Antivir Chem Chemother ; 26: 2040206618757636, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29436843

RESUMEN

Background The replacement of ß,γ-pyrophosphate by ß,γ-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5'-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir). Methods Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp). Results Searching for nucleoside 5'-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM). Conclusion PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , Inhibidores de la Transcriptasa Inversa/farmacología , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Transcriptasa Inversa del VIH/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad
19.
Nucleosides Nucleotides Nucleic Acids ; 37(2): 89-101, 2018 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-29376769

RESUMEN

The title compound is an excellent substrate for E. coli PNP, as well as for its D204N mutant. The main product of the synthetic reaction is N9-riboside, but some amount of N7-riboside is also present. Surprisingly, 1,N6-ethenoadenine is also ribosylated by both wild-type and mutated (N243D) forms of calf PNP, which catalyze the synthesis of a different riboside, tentatively identified as N6-ß-D-ribosyl-1,N6-ethenoadenine. All ribosides are susceptible to phosphorolysis by the E. coli PNP (wild type). All the ribosides are fluorescent and can be utilized as analytical probes.


Asunto(s)
Adenina/análogos & derivados , Proteínas de Escherichia coli/química , Nucleósidos de Purina/síntesis química , Purina-Nucleósido Fosforilasa/química , Adenina/síntesis química , Adenina/química , Biocatálisis , Cinética , Estructura Molecular , Mutación , Nucleósidos de Purina/química , Espectrometría de Fluorescencia
20.
Pharm Dev Technol ; 23(9): 890-899, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28535125

RESUMEN

The objectives of this study were to prepare cocrystal composed of adefovir dipivoxil (AD) and stearic acid (SA) and to investigate the enhanced properties of the cocrystal. The cocrystal was prepared by antisolvent precipitation and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). The enhanced properties were evaluated by dissolution testing, permeability studies, and powder rheology analysis. The AD raw material has a cuboid-like crystal and the cocrystal has a needle shape. In the FT-IR study, there were bathochromic shifts caused by the hydrogen bonding. The melting point of the cocrystal was 52.9 °C, which was lower than that of AD. The XRPD pattern also had distinct differences, supporting the formation of a new crystalline form. The cocrystal showed changes in the lattice energy and the solvation strength, which caused an enhanced dissolution. The permeability was increased due to the SA, which acts as a P-gp inhibitor. The tabletability was enhanced due to the altered crystal habit. In conclusion, cocrystal containing AD and SA was successfully prepared, presenting advantages such as enhanced solubility, tabletability, and permeability. The use of the cocrystal is a desirable approach for the improved physicochemical properties.


Asunto(s)
Adenina/análogos & derivados , Fenómenos Químicos , Química Farmacéutica/métodos , Organofosfonatos/síntesis química , Ácidos Esteáricos/síntesis química , Adenina/análisis , Adenina/síntesis química , Adenina/farmacocinética , Microscopía Electrónica de Rastreo/métodos , Organofosfonatos/análisis , Organofosfonatos/farmacocinética , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Ácidos Esteáricos/análisis , Ácidos Esteáricos/farmacocinética , Difracción de Rayos X/métodos
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