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Thymidine Analogues (thymidine + analogue)
Selected AbstractsMycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors: Biological Evaluation and Conformational Analysis of 2,- and 3,-Modified Thymidine AnaloguesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 15 2003Philippe Van Rompaey Abstract Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a,b, 6a,b, 7a,b, and 8a,b, modified in 2,- and 3,-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. Ki between 118 and 1260 ,M). This prompted us to investigate the conformational features of these nucleosides. We concluded that compounds of this series, especially 8a,b, are strongly biased towards the "Northern" furanose ring conformation, whereas X-ray crystallography reveals a preference of TMPKmt for the opposite "Southern" conformers. This paper covers the synthesis, biological evaluation and conformational features (i.e. preferred ring puckering) of the 2,- and 3,-modified dT analogues. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Prevalence of the mutational pattern E44D/A and/or V118I in the reverse transcriptase (RT) gene of HIV-1 in relation to treatment with nucleoside analogue RT inhibitorsJOURNAL OF MEDICAL VIROLOGY, Issue 3 2002Brigitte Montes Abstract It has been reported that a new pattern of mutations, E44D/A and/or V118I, in the reverse transcriptase (RT) gene of HIV-1 confers a moderate level of resistance to lamivudine in the absence of the M184V mutation. The prevalence of this mutational pattern was studied in HIV-1 isolates obtained from 280 patients. These mutations were not identified in the RT sequences from 23 antiretroviral-naive patients but were detected in 82 (31.9%) of the 257 RT sequences obtained from nucleoside reverse transcriptase inhibitors (NRTI)-experienced patients. Mutation at codon 44 was identified in 41 patients (7 mutations E44A and 34 mutations E44D), mutation V118I was identified in 73 patients and a combination of mutations at codons 44 and 118 was found in 32 patients. Multivariate analysis showed an association between the E44D/A and/or V118I mutational pattern and the RT mutations D67N, T69D, L210W, and T215Y/F. No relationship was observed between this mutational pattern and the lamivudine-specific resistance mutation M184V. The prevalence of these mutations increased significantly with the number of drug regimens experienced and a prevalence of 42.4% was observed in patients who had received ,,4 antiretroviral regimens. A relationship was found between the E44D/A and/or V118I mutational pattern and experience with didanosine or stavudine but not with lamivudine. The results suggest that the development of the E44D/A and/or V118I mutational pattern is frequent in patients treated with NRTIs. Thymidine analogues and didanosine, but not lamivudine, could promote the development of these mutations. J. Med. Virol. 66:299-303, 2002. © 2002 Wiley-Liss, Inc. [source] Preparation and biodistribution of [125I]Melphalan: a potential radioligand for diagnostic and therapeutic applicationsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2010A. M. Amin Abstract This paper addresses the development of a new radiopharmaceutical for cancer imaging and therapy. The optimization of the labeling conditions of thymidine analogue, melphalan, with125I is described. High radiochemical yield 96.8% was obtained by reacting 0.2,mg melphalan with 125I in the presence of choloramin-T as oxidizing agent in 0.5,M phosphate buffer, pH 7, at 70°C for 15,min. Preliminary in vivo study was done in non-tumor bearing mice. The results revealed that this new tracer,125I-melphalan, has a high affinity to be localized in the tumor site for a long period, which indicates the specificity of this tracer to the tumor cells. The labeled compound was cleared quickly from most of the body organs. These findings suggest that 125I-melphalan allows imaging and treatment of cancer. 125I-melphalan meets most of the requirements necessary to be used as a successful diagnostic and therapeutic agent: it is a low-molecular-weight molecule that diffuses readily in the tissues, and dose not induce an antibody response. Copyright © 2009 John Wiley & Sons, Ltd. [source] Expression of a Rho Guanine Nucleotide Exchange Factor, Ect2, in the Developing Mouse PituitaryJOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2010M. S. Islam The pituitary gland is a highly mitotically active tissue after birth. Various cell types are known to undergo proliferation in the anterior pituitary. However, little is known about the mechanisms regulating mitotic activity in this tissue. When searching for genes specifically expressed in the pituitary gland among those that we previously screened in Drosophila, we found epithelial cell-transforming gene 2 (Ect2). Ect2 is a guanine nucleotide exchange factor for Rho GTPases, which is known to play an essential role in cytokinesis. Although there have been many cellular studies regarding the function of Ect2, the temporal and spatial expression patterns of Ect2 in vivo have not been determined. In the present study, we examined the postnatal developmental expression of Ect2 in the mouse pituitary. Enhanced Ect2 expression was detected in the mouse pituitary gland during the first 3 weeks after birth, which coincided well with the period of rapid pituitary expansion associated with increased growth rate. Immunostaining analysis showed that Ect2-expressing cells were distributed in the anterior and intermediate lobes, but not the posterior lobe, of the pituitary. These Ect2-expressing cells frequently incorporated the thymidine analogue, EdU (5-ethynyl-2,-deoxyuridine), indicating that these cells were mitotically active. Taken together, the results demonstrate the functional role of Ect2 in postnatal proliferating cells in the two lobes of the pituitary, thereby suggesting roles in developmental growth of the mammalian pituitary. [source] Use of radiolabelled iododeoxyuridine as adjuvant treatment for experimental tumours of the liverBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 10 2003J. S. Zager Background The aim of the study was to determine whether hepatic regeneration stimulates growth of tumour residing within the liver, and whether a difference in the rate of DNA synthesis in liver and tumour may be used to target cancer using the radiolabelled thymidine analogue 5-iodo-2,-deoxyuridine (IUdR). Methods Partial hepatectomy was performed on Buffalo rats bearing solitary nodules of syngeneic Morris hepatoma. Liver and tumour DNA synthesis was measured by incorporation of radioactive IUdR. [125I]IUdR was tested as an adjuvant therapy after hepatectomy in Buffalo rats bearing diffuse microscopic Morris hepatomas to simulate the clinical situation. Results Liver regeneration enhanced liver and tumour DNA synthesis as measured by incorporation of radioactive IUdR. Liver DNA synthesis returned to baseline by 7 days, whereas tumour DNA synthesis remained above baseline level. Hepatectomy enhanced the growth of microscopic liver tumours. [125I]IUdR (250 µCi or 1 mCi/kg) administered 4 days after hepatectomy significantly reduced tumour growth without signs of systemic toxicity or liver dysfunction. Conclusion The local environment of the regenerating liver stimulates tumour growth. The thymidine analogue [125I]IUdR may be used preferentially to target tumour DNA synthesis in the regenerating liver, and may prove useful as an adjuvant therapy for hepatic tumours after surgical resection. Copyright © 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Low doses of bromo- and iododeoxyuridine produce near-saturation labeling of adult proliferative populations in the dentate gyrusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Kevin A. Burns Abstract Cell proliferation can be detected by the incorporation of tritiated thymidine (3H-dT) or halopyrimidines during DNA synthesis in progenitor cells. Administration of two thymidine analogues at different times can further determine the cell-cycle kinetics of proliferating cells. Traditionally, this was done by combining bromodeoxyuridine (BrdU) immunocytochemistry and 3H-dT autoradiography, or by BrdU and iododeoxyuridine (IdU) double-labeling using two mouse antibodies. However, these methods either require lengthy exposure time or involve complicated histological procedures for differentiating between two antibodies of the same species. Here we report a simple and reliable method of distinguishing BrdU- and IdU-labeled cells by immunofluorescence. This method uses a mouse monoclonal antibody that recognizes both BrdU and IdU and a rat anti-BrdU antibody that has no cross-reactivity with IdU. When combined with species-specific secondary antibodies that are conjugated to different fluorophores, this method identifies BrdU- and IdU-incorporation as doubly and singly labeled cells, respectively. This method has broad applications. First, we demonstrate that this method can distinguish mouse cortical neurons generated on different embryonic days. Second, by administering IdU and BrdU at varying intervals, we used this method to calculate that the length of S-phase of neural progenitor cells in the adult mouse dentate gyrus is approximately 6 h. Finally, we show that a six-fold higher concentration of IdU detects only 10% more cells than the standard dose of BrdU (50 mg/kg) using the double-labeling method. These results suggest that the standard dose of BrdU is sufficient to label the majority of proliferative populations in the S-phase in pulse labeling experiments. [source] European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV,HIV MEDICINE, Issue 2 2008JD Lundgren Background Metabolic diseases are frequently observed in HIV-infected persons and, as the risk of contracting these diseases is age-related, their prevalence will increase in the future as a consequence of the benefits of antiretroviral therapy (ART). Summary of guidelines All HIV-infected persons should be screened at regular intervals for a history of metabolic disease, dyslipidaemia, diabetes mellitus, hypertension and alteration of body composition; cardiovascular risk and renal function should also be assessed. Efforts to prevent cardiovascular disease will vary in intensity depending on an individual's absolute risk of ischaemic heart disease and should be comprehensive in nature. Lifestyle interventions should focus on counselling to stop smoking, modify diet and take regular exercise. A healthy diet, exercise and maintaining normal body weight tend to reduce dyslipidaemia; if not effective, a change of ART should be considered, followed by use of lipid-lowering medication in high-risk patients. A pre-emptive switch from thymidine analogues is recommended to reduce the risk of development or progression of lipoatrophy. Intra-abdominal fat accumulation is best managed by exercise and diet. Prevention and management of type 2 diabetes mellitus and hypertension follow guidelines used in the general population. When using medical interventions to prevent and/or treat metabolic disease(s), impairment of the efficacy of ART should be avoided by considering the possibility of pharmacokinetic interactions and compromised adherence. Specialists in HIV and specialists in metabolic diseases should consult each other, in particular in difficult-to-treat cases. Conclusion Multiple and relatively simple approaches exist to prevent metabolic diseases in HIV-infected persons; priority should be given to patients at high risk of contracting these diseases. [source] Human immunodeficiency virus,hepatitis C coinfection: swapping new problems for newer onesINTERNAL MEDICINE JOURNAL, Issue 7 2001J. Sasadeusz Abstract Recent successes in HIV therapy have uncovered other health problems for HIV-infected individuals. Hepatitis C has become an especially significant problem, partly due to its faster progression in an immunocompromised setting. In addition, the higher viral loads in coinfected patients likely result in more efficient perinatal and perhaps even sexual transmission. Therapy has largely been neglected, despite data suggesting its efficacy in HIV,HCV coinfected patients. Studies of combination interferon and ribavirin studies are lacking, although underway. A major concern is the potential inactivation of certain thymidine analogues by ribavirin. Some antiretroviral therapies, such as ritonavir, indinavir and nevirapine, may enhance liver toxicity in coinfected patients and should be avoided if possible. The role of chronic low-grade liver function abnormalities remains uncertain and requires further investigation. (Intern Med J 2001; 31: 418,421) [source] In vitro analysis of synergism and antagonism of different nucleoside/nucleotide analogue combinations on the inhibition of human immunodeficiency virus type 1 replication,JOURNAL OF MEDICAL VIROLOGY, Issue 2 2009M. Perez-Olmeda Abstract In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T-cell lines. PBMCs were infected with a full-length HIV-1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV,+, d4T), lamivudine,+,abacavir (3TC,+,ABC), lamivudine,+,didanosine (3TC,+,ddI), lamivudine,+ stavudine (3TC,+,d4T), tenofovir,+,stavudine (TDF,+,d4T), tenofovir,+,didanosine (TDF,+,ddI), tenofovir,+,abacavir (TDF,+,ABC), tenofovir,+, lamivudine (TDF,+,3TC), tenofovir,+,zidovudine (TDF,+,ZDV), stavudine,+,didanosine (d4T,+,ddI), zidovudine,+,lamivudine (ZDV,+,3TC), abacavir,+, didanosine (ABC,+,ddI), zidovudine,+,didanosine (ZDV,+,ddI), and abacavir,+,stavudine (ABC,+, d4T). The effect of combining two drugs was evaluated with a quantitative method based on the median-effect principle of Chou and Talalay. A synergistic effect was observed with combinations containing TDF and ZDV or d4T, d4T and ddI and ZDV plus 3TC. In contrast, combinations including TDF,+,ddI, 3TC,+,ddI, ABC,+,ddI, and ZDV,+,ddI showed an antagonistic effect on the inhibition of viral replication at all levels of inhibition tested. Lower antagonistic effect was also found in drug combinations that included 3TC,+,ABC, 3TC,+,TDF, 3TC,+,d4T, and TDF,+, ABC. In conclusion, the method developed allows to measure in vitro the effect of different combinations of two NRTIs on HIV replication. The results suggest that combined therapy including TDF with thymidine analogues may be considered for future therapeutic options in contrast to clearly antagonistic combinations such us TDF plus ddI or 3TC plus ddI, that would explain virological failure in clinical studies when these combinations were used. J. Med. Virol. 81:211,216, 2009. © 2008 Wiley-Liss, Inc. [source] | ||||||||||||||||