RESUMO
A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC50 was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile.
Assuntos
Antineoplásicos , Antioxidantes , Humanos , Antioxidantes/química , Linhagem Celular Tumoral , Antineoplásicos/química , Protetores Solares/farmacologia , Protetores Solares/química , Benzotiazóis/química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de CélulasRESUMO
In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or -SO3H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10, bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Pele/efeitos dos fármacos , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Pele/efeitos da radiação , Relação Estrutura-Atividade , Raios Ultravioleta/efeitos adversosRESUMO
The incidence of skin cancer is increasing both because of climate change and the increase in pollution than people's incorrect habits of sun exposure. In these regards, sunscreen and photoprotection are essential tools in consenting the benefits induced by safe solar light exposition and skin cancer prevention. In this work, a new class of sunscreen filter was synthesized by chemical combination of a physical filter (ZnO) and Oxisol (dihydroxyphenyl benzimidazole carboxylic acid), an antioxidant molecule with booster effect. In this work, a new class of filters with new properties was achieved by direct functionalization of particles surface. A full characterization of this multifunctional ingredient (ZnO-Ox) was conducted: Compared with the simple mixture, the new filter acts as a multifunctional molecule showing a higher Sun Protection Factor (SPF), a better cytotoxic profile (MTT and NRU assay), and anti-acne activity. A strong reduction of photocatalytic activity of ZnO was observed, also improving the safety profile.
Assuntos
Antioxidantes , Benzimidazóis , Protetores Solares , Raios Ultravioleta/efeitos adversos , Óxido de Zinco , Células 3T3 , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Humanos , Camundongos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controle , Luz Solar/efeitos adversos , Protetores Solares/química , Protetores Solares/farmacologia , Óxido de Zinco/química , Óxido de Zinco/farmacologiaRESUMO
An ever-increasing incidence of skin neoplastic diseases is registered. Therefore, it is important to protect the skin from the UV radiation that reaches the epidermis and dermis but also to block ROS generated by them. Our attention was attracted in developing new compounds provided with both UV filtering and antioxidant capacities. To this end, 2-phenyl-1H-benzimidazole-5-sulfonic acid (PBSA), a known UV filter, was selected as lead compound for its lack of antioxidant activity, high water solubility and good safety profile. PBSA was sequentially modified introducing hydroxyls on the phenyl ring and also substituting the functional group in position 5 of the benzimidazole ring. At the end of the synthetic study, a new, very potent class of antioxidants has been obtained. Surprisingly some of the developed molecules, while devoid of significant UV-filtering activity was endowed with potent UV-filtering booster capability if associated with known commercial UVB and UVA filters.
Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Sequestradores de Radicais Livres/farmacologia , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Protetores Solares/síntese química , Protetores Solares/químicaRESUMO
Over the last years, hyaluronic acid (HA) injectable dermal fillers (DFs) have become the most popular agents for soft tissue contouring and volumizing. HA fillers are characterized by most of the properties that an ideal DF should have, due to HA unique chemical-physical properties, biocompatibility, biodegradability, and versatility. Therefore, HA DFs have revolutionized the filler market with a high number of products, which differ in terms of HA source, cross-linkage (agent and degree), HA concentration, hardness, cohesivity, consistency, inclusion or lack of anesthetic, indication, and longevity of correction. The article first provides a general introduction to DF world, and an overview of the different materials is available for fillers. Second, it describes the characteristics and the peculiarities of HA fillers, their differences from the other available materials, and therefore the reasons at the base of their success. Moreover, an update regarding the main Food and Drug Administration (FDA) approved fillers is presented.
Assuntos
Preenchedores Dérmicos/uso terapêutico , Ácido Hialurônico/uso terapêutico , Implantes Absorvíveis , Materiais Biocompatíveis , Colágeno/uso terapêutico , Técnicas Cosméticas , Preenchedores Dérmicos/efeitos adversos , Preenchedores Dérmicos/química , Durapatita/uso terapêutico , Face , Humanos , Ácido Hialurônico/efeitos adversos , Ácido Hialurônico/química , Poliésteres/uso terapêutico , Polimetil Metacrilato/uso terapêutico , Reologia , Silicones/uso terapêutico , Envelhecimento da PeleRESUMO
This research investigated plant extracts as a source of potential new actives in the nutritional, cosmetic, and pharmaceutical fields. Moringa oleifera, which is extensively known for its nutritional properties, has been investigated in this work by preparation, characterization, and evaluation of the antioxidant (FRAP, DPPH, ORAC, and PCL test), antifungal, photoprotective, and cytotoxicity profile against human melanoma Colo38 cell line of two different extracts (hydroalcoholic and methanolic) and one infusion of dry leaves collected from Paraguay in four distinct harvest times (February, March, April, and May 2017). The outcomes of this study highlight Moringa oleifera as a potential ally to counteract skin aging and oxidative stress, as indicated by the favorable antioxidant profile of the extracts and infusions of Paraguay, which was, in all cases, superior to that provided by the same plant species when collected from Senegal. Moreover, some samples were more efficient in preventing the photodegradation of UVA filter butyl methoxydibenzoylmethane (Avobenzone) compared to commercial filters, thus suggesting an interesting future role as natural additives in sunscreens.
RESUMO
There are only a limited number of molecules in a cosmetic formulation, which can passively cross the stratum corneum and be absorbed into the skin layers. However, some actives should never cross the skin in large concentrations due to their potential for side effects, for example, sunscreens. Artificial intelligence is gaining an increasing role as a predictive tool, and in this regard, we selected the Formulating for Efficacy® Software to forecast the changes in bioavailability of selected topical cosmetic compounds. Using the Franz diffusion cell methodology, various oils were selected as those with low release capability, and these were compared to those suggested by the software in Benzophenone-3-containing formulations. The software was able to predict the lipophilic phases, which, if utilized in the emulsion, were stable and sometimes even more pleasant in appearance and consistency than the reference emulsions prepared by the formulator. To date, however, Formulating for Efficacy® Software still has limitations as far as predicting the hydrophilic phase, as well as not being able to choose the emulsifier or the preservative system.
RESUMO
Skin diseases often give multifactorial damages; therefore, the development of multifunctional compounds represents a suitable approach especially against disorders that are induced by oxidative stress. Thus, taking into account the successful results we achieved on benzimidazoles, we have devised a new series of isosteric benzothiazoles and investigated their antioxidant, photoprotective, antifungal and antiproliferative activity. Particular attention has been paid to synergistic antioxidant and photoprotective properties. For compounds 9a and 10a, a multifunctional profile was outlined, supported by an excellent filtering capacity, mainly UVB, which has higher capacities than those of the reference PBSA which is currently in the market as a UV sunscreen filter. The two compounds were also the best in terms of growth inhibition of dermatophytes and Candida albicans, and 10a also showed good antioxidant activity. Furthermore, 9a was also effective on melanoma tumor cells (SK-Mel 5), making these compounds good candidates in the development of new skin protective and preventive agents.
RESUMO
Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the half-life and consequently increase performance, native HA has been modified through cross-linking reactions with a natural and biocompatible amino acid, Ornithine, to overcome the potential toxicity commonly associated with traditional linkers. 2-chloro-dimethoxy-1,3,5-triazine/4-methylmorpholine (CDMT/NMM) was used as an activating agent. The new product (HA-Orn) was extensively characterized to confirm the chemical modification, and rheological analysis showed a gel-like profile. In vitro degradation experiments showed an improved resistance profile against enzymatic digestions. Furthermore, in vitro cytotoxicity studies were performed on lung cell lines (Calu-3 and H441), which showed no cytotoxicity.
RESUMO
Skin cancer is the most common malignant cancer with an incidence of 1 million cases/year. It is well known that exposure to UV radiation from sunlight leads the most frequent risk factors for several skin disorders including skin cancer. Sunscreen filters represent a valid protection against dangerous effects derived from UV radiation, and they can be divided in organic and inorganic UV filters. Adding, at the product formulation, molecules with booster effect, or also substances that can increase the protecting effectiveness via synergic mechanisms, can further enhance their protection activity. Moreover, this approach leads to develop formulations with high SPF (Sun Protection Factor) with a reduced content of UV filters, this is in line with the recent decisions of yet a few countries (Palau, Thailand, Philippines, and Hawaii) to ban some sunscreen filters to preserve marine environments (i.e., reef). In this work, a new class of sunscreen UV filters has been synthesized, by means the combination of physical filter and Oxisol, an antioxidant molecule with booster effect. In this study, the synthesis of new physical multifunctional ingredients is reported, by means the direct surface functionalization of inorganic filters (in particular TiO2) with Oxisol. In this study, the full characterization of these multifunctional ingredients is also reported, in addition to the cytotoxicity tests, the photocatalytic activity and the rheological properties involved on skin application.
RESUMO
The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2',3',5' tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3-(2',3',5'-tri-O-benzoyl-beta-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides.
Assuntos
Inosina/análogos & derivados , Nucleosídeos de Pirimidina/síntese química , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Desenho de Fármacos , Inosina/síntese química , Inosina/química , Inosina/farmacologia , Espectroscopia de Ressonância Magnética , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Toiocamicina/análogos & derivados , Toiocamicina/síntese química , Toiocamicina/química , Tubercidina/análogos & derivados , Tubercidina/síntese química , Tubercidina/química , Replicação Viral/efeitos dos fármacosRESUMO
We report a preliminary study concerning the encapsulation modalities in nanoparticles of the anti-ischemic drug N6-cyclopentyladenosine (CPA) and its pro-drug 5'-octanoyl-CPA (Oct-CPA). The release of these compounds and the related pro-drug stability effects in human whole blood have been tested. Moreover, the influence of the delivery systems on CPA interaction toward human adenosine A1 receptor has been analysed. The nanospheres were prepared by nanoprecipitation or double emulsion solvent evaporation method using poly(lactic acid) and recovered by gel filtration or ultracentrifugation or dialysis. Free and encapsulated Oct-CPA was incubated in fresh blood and its stability was analysed with HPLC. Quite spherical nanoparticles with mean diameters ranging between 210+/-50 and 390+/-90 nm were obtained. No encapsulation occurred when CPA was used. Satisfactory results concerning drug content (0.1-1.1% w/w) and encapsulation efficiency (6-56%) were achieved when Oct-CPA was employed. The controlled release of the pro-drug was achieved, being released within a range of 1-4 h, or very slowly, depending on nanoparticle preparations. The hydrolysis rate of Oct-CPA in human whole blood appeared stabilized in human whole blood with modalities related to the release patterns. The presence of all nanoparticle preparations did not interfere with CPA interaction at its action site.
Assuntos
Adenosina/administração & dosagem , Adenosina/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Nanotubos/química , Receptor A1 de Adenosina/metabolismo , Implantes Absorvíveis , Adenosina/análogos & derivados , Adenosina/sangue , Animais , Células CHO , Cricetinae , Cricetulus , Preparações de Ação Retardada/química , Difusão , Humanos , Ácido Láctico/química , Taxa de Depuração Metabólica , Nanotubos/ultraestrutura , Tamanho da Partícula , Poliésteres , Polímeros/química , Vasodilatadores/administração & dosagem , Vasodilatadores/sangue , Vasodilatadores/farmacocinéticaRESUMO
GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-D-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable "pro-drug approach" was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.
Assuntos
Glicina/antagonistas & inibidores , Glicina/farmacologia , Indenos/metabolismo , Indenos/farmacologia , Pró-Fármacos/síntese química , Pirrolidinas/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Glicina/uso terapêutico , Indenos/uso terapêutico , Monossacarídeos/química , Monossacarídeos/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Pró-Fármacos/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Receptores de N-Metil-D-Aspartato/uso terapêuticoRESUMO
Continuing our investigations on inhibitors of ribonucleotide reductase (RNR), the crucial enzyme that catalyses the reduction of ribonucleotides to deoxyribonucleotides, we have now prepared and evaluated 5'-phosphonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contribution to biological activity of diphosphate mimic moieties. A molecular modelling study has been conducted on the RNR R1 subunit, in order to verify the possible interaction of the proposed bioisosteric moieties. The study compounds were finally tested on the recombinant murine RNR showing a degree of inhibition that ranged from 350 microM for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 microM for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 microM concentrations, whereas ADP analogue 5'-N-[(diethyl-phosphon) acetyl]adenosine (amide) and 5'-deoxy-5'-N-(phosphon-acetyl)adenosine sodium salt (amide) showed a moderate inhibitory activity (EC50: 48 microM) against HSV-2 and a modest inhibitory activity (EC50: 110 microM) against HIV-1, respectively.
Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Ésteres/química , Ácido Fosfonoacéticos/análogos & derivados , Ácido Fosfonoacéticos/farmacologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Amidas/química , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nucleosídeos/química , Ácido Fosfonoacéticos/química , Ribonucleotídeo Redutases/metabolismoRESUMO
Because of the health implications of resveratrol and piceid, which are widely present in foods, we focused our attention on the development of a highly efficient methodology for their characterization and measurement. On the basis of our experience in capillary electrophoresis for separation of polyphenolic compounds, we developed a general analytical method for piceid identification which was also applicable to complex natural mixtures such as red wine. In view of its very limited availability from natural sources, we first directed our attention to the development of a synthetic route suitable to produce an adequate amount of polydatin (piceid or resveratrol 3-O-beta-D-glucopyranoside). The latter was synthesized by a new one-step procedure which afforded the expected product in a good yield. The studied compounds were also investigated for their stability to UV irradiation.
Assuntos
Eletroforese Capilar , Glucosídeos/análise , Glucosídeos/síntese química , Estilbenos/análise , Estilbenos/síntese química , Estabilidade de Medicamentos , Resveratrol , Vinho/análiseRESUMO
Following the recent output of scientific publications in the matter of synergic activity between different antioxidants, we have undertaken the present study with the aim to synthesize new molecules with radical-scavengers activity based on the conjugation of bioactive portions (i.e. phenols, cysteine, methionine or tyrosine), characterized by different structures and mechanisms of action, to promote the simultaneous quenching of different radical species in the site of the oxidative damage. In this context, derivatives of phenolic acid, aminoacids and dopamine have been also prepared. The newly synthesized compounds were evaluated in vitro applying specific and complementary antioxidant test such as DPPH assay and ORAC test. As emerged from the evaluation, prerequisites for the activity of the synthesized molecules were: i) the maintenance of at least two hydroxylic groups on the aromatic moiety of phenolic portion, ii) the presence of a spacer between the aromatic moiety and the carbonilic group.
Assuntos
Aminoácidos/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Desenho de Fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Polifenóis/química , Compostos de Bifenilo/farmacologia , Dopamina/química , Humanos , Indicadores e Reagentes/farmacologia , Estrutura Molecular , Picratos/farmacologia , Espécies Reativas de Oxigênio/química , Relação Estrutura-AtividadeRESUMO
During a random screening of representative libraries of nucleoside analogues we discovered that the adenine derivatives FEVB28 and FEG118 were Flaviviridae inhibitors endowed with potency comparable, if not superior, to that of ribavirin. Those studies prompted us to design a new class of protected nucleoside analogs, reported herein, which displays interesting anti-bovine viral diarrhea virus (BVDV) activity and low cytotoxicity in cell-based assays (4, 23, 29 EC(50): 14, 11, 26 microM respectively, CC(50)>100 microM) and appreciable activity in enzyme assays against the RNA dependent RNA polymerase (RdRp) of BVDV (4, 23, 29, RdRp inhibition activity 27, 16, 15 microM respectively). A molecular modeling study was also carried out to highlight the possible interactions between this compounds class and the corresponding hepatitis C virus (HCV) enzyme.
Assuntos
Nucleotídeos de Adenina/síntese química , Nucleotídeos de Adenina/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Flaviviridae/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Bovinos , Linhagem Celular , Cromatografia em Camada Fina , Simulação por Computador , Cricetinae , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Entropia , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Sais de Tetrazólio , TiazóisRESUMO
Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.
Assuntos
Antioxidantes/farmacologia , Benzoquinonas/farmacologia , Cromanos/farmacologia , Fibroblastos/efeitos dos fármacos , Ataxia de Friedreich/patologia , Substâncias Protetoras/farmacologia , Vitamina E/farmacologia , Animais , Antioxidantes/química , Benzoquinonas/química , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Fibroblastos/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Substâncias Protetoras/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/análogos & derivados , Vitamina E/químicaRESUMO
Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains (acyl or alkyl entities) at the 2' position of araT and BVaraU, nucleoside analogues naturally endowed with a low TK2 affinity. These derivatives showed a competitive inhibitory activity against TK2 in micromolar range. BVaraU nucleoside analogues, modified on the 2'-O-acyl chain with a terminal N-Boc amino-group, conserved or increased the inhibitory activity against TK2 (7l and 7m IC(50): 6.4 and 3.8 microM, respectively). The substitution of an ester for a carboxamide moiety at the 2' position of araT afforded a consistent reduction of the inhibitory activity (25, IC(50): 480 microM). On the contrary, modifications at 2'-OH position of araC and araG, have provided inactive derivatives against TK2 and dGK, respectively. The biological activity of a representative compound, 2'-O-decanoyl-BVaraU, was also investigated in normal human fibroblasts and was found to impair mitochondrial function due to TK2 inhibition.