Potential radiosensitizing agents. Dinitroimidazoles

Agrawal, Krishna C.; Bears, Kathleen B.; Sehgal, Raj K.; Brown, J. N.; Rist, P. E.; Rupp, W. Dean

doi:10.1021/jm00191a025

Cited by 53 publications

(27 citation statements)

References 9 publications

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“…A series of bicyclic nitroimidazofurans, originally investigated as radiosensitizers for use in cancer chemotherapy (1), were found to possess activity against cultured replicating Mycobacterium tuberculosis and had significant in vivo activity in a murine infection model (3,17,25). A subsequent series of 3-substituted nitroimidazopyrans (NAPs) were synthesized, and more than 100 compounds were found to possess substantial antitubercular activity.…”

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confidence: 99%

Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

Lenaerts

Gruppo

Marietta

et al. 2005

Antimicrob Agents Chemother

293

282

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This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrugresistant clinical isolates and was found to be highly active against all isolates (MIC < 1 g/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 g/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.Therapy for tuberculosis (TB) is arduous due to its long duration and the need to use multidrug regimens. The current standard regimen of isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) requires 6 to 8 months of daily treatment. In part due to noncompliance with treatment, therapy is now further complicated by the emergence of drug-resistant strains, with the global prevalence of drug resistance being from 1 to 3% (27). A further, equally important issue with tuberculosis therapy is the treatment of patients in which the infection may be in a latent state. Supposedly, 1:3 people throughout the world harbor latent bacilli, which have the potential to reactivate and cause active disease (21, 23). Current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, and therefore, there is an urgent need for novel drugs that are also effective against persisting or latent bacterial infections, as well as those that can overcome the increasing problem of drug resistance.A series of bicyclic nitroimidazofurans, originally investigated as radiosensitizers for use in cancer chemotherapy (1), were found to possess activity against cultured replicating Mycobacterium tuberculosis and had significant in vivo activity in a murine infection model (3,17,25). A subsequent series of 3-substituted nitroimidazopyrans (NAP...

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mentioning

confidence: 99%

Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

Lenaerts

Gruppo

Marietta

et al. 2005

Antimicrob Agents Chemother

293

282

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“…Since detailed information such as pharmacology, formulation and potential toxicity of many approved drugs is readily available these drugs could be ready for clinical trials quickly. A bicyclic nitroimidazofuran compound, PA-824, which had been investigated as a potential radio-sensitizing agent for use in cancer radiotherapy, 44 was later found to display anti-TB activities in both in vitro and in vivo models. 45 Here, we report synthesis of small organic compounds from a celecoxib pharmacophore, and their repurposing and identification of potential anti-TB hits through bioluminescence-based high-throughput screening method.…”

Section: Discussionmentioning

confidence: 99%

Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore

Salunke

Azad

Kapuriya

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Tais derivados têm diferentes estabilidades e reatividades dependendo dos substituintes do anel aromático e do pH 43 . Apesar de os nitroimidazóis, tais como o metronidazol (2) e o misonidazol (3), possuírem seletividade para células em hipóxia, eles apresentam baixa potência e, conseqüentemente, elevadas doses são necessárias para exercerem uma ação citotóxica [55][56][57][58] . Em função disto, novos compostos desta classe estão sendo estudados.…”

Section: Nitroimidazóisunclassified

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

Oliveira¹,

Alves²

2002

Quím. Nova

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Recebido em 17/8/01; aceito em 27/2/02 BIOREDUCTIVE ANTINEOPLASTIC AGENTS: A NEW APPROACH TO THE TREATMENT OF SOLID TUMORS. A problem often encountered in cancer therapy is the presence of tumor cell subpopulation that are resistant to treatment. Solid tumors frequently contain hypoxic cells that are resistant to killing by ionizing radiation and also by many chemotherapeutic agents. However, these hypoxic cells can be exploited for therapy by non-toxic hypoxic-activated prodrugs. Bioreductive drugs require metabolic reduction to generate cytotoxic metabolites. This process is facilitated by appropriate reductases and the lower oxygen conditions present in solid tumors. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.Keywords: solid tumor; hypoxic cells; bioreductive prodrugs. INTRODUÇÃOO câncer é basicamente uma doença de células, caracterizada por um desvio dos mecanismos de controle que dirigem a proliferação e a diferenciação celulares. As células que sofreram transformação neoplásica proliferam excessivamente e formam tumores locais que podem comprimir ou invadir estruturas normais adjacentes 1 . Progressos importantes na quimioterapia foram registrados na área da biologia molecular e celular, o que facilitou, juntamente com o maior entendimento do mecanismo de ação de muitas substâncias, a aplicação mais racional dos quimioterápicos e o planejamento de novos fármacos. Muitas das substâncias citotóxicas mais potentes atuam em fases específicas do ciclo celular e, conseqüentemente, só exercem a sua atividade contra células que se encontram em processos de divisão 2 . Sendo assim, as neoplasias malignas humanas que, atualmente, são mais suscetíveis ao tratamento quimioterápico e, freqüentemente, curadas, são aquelas que possuem alta porcentagem de células em processo de divisão. Os tumores sólidos, que apresentam divisão celular relativamente lenta, tais como os carcinomas de pulmão, cólon e mama, constituem mais de 90% de todos os tipos de câncer do homem. Estes tipos de neoplasias, em geral, respondem pouco aos agentes quimioterápicos existentes e o tratamento curativo, utilizando qualquer umas das modalidades terapêu-ticas (cirurgia, radioterapia, quimioterapia, imunoterapia e fototerapia dinâmica) ou mesmo a combinação das diversas modalidades, é extremamente difícil 3 . Além disso, uma outra limitação da quimioterapia é que a maioria dos fármacos antineoplásicos é altamente tóxica para o paciente e deve ser administrada com extremo cuidado 2,4 . CARACTERÍSTICAS DOS TUMORES SÓLIDOSAo contrário da percepção popular, a estrutura de um tumor não consiste, simplesmente, em um aglomerado de células em constante proliferação. As células neoplásicas freqüentemente ocupam menos da metade do volume total do tumor. Os vasos sangüíneos que se entrelaçam dentro da massa tumoral preenchem 1 a 10% do volume do tumor. O espaço restante é preenchido por matriz rica em colágeno o interstício que envolve as células neoplásicas e pode separá-las da vascularizaçã...

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Potential radiosensitizing agents. Dinitroimidazoles

Cited by 53 publications

References 9 publications

Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

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