Carcinogenicity Testing of Novel Phenanthrene Diketoacid Anti-HIV Agents

新型菲二酮酸抗 HIV 药物的致癌性测试

• 批准号: 7496377
• 负责人: John K Buolamwini
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496377
• 关键词: AIDS chemotherapy; AIDS/HIV problem; Acids; Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antimalarials; Aromatic Polycyclic Hydrocarbons; Butyric Acid; Butyric Acids; Carcinogenicity Tests; Carcinogens; Class; Clinical Trials; Cultured Cells; Development; Drug resistance; Electrons; Enzymes; Face; Goals; Grant; HIV; HIV Integrase; HIV Integrase Inhibitors; HIV Protease Inhibitors; Highly Active Antiretroviral Therapy; Human; Hydrocarbons; In Vitro; Inhibitory Concentration 50; Integrase; Integrase Inhibitors; Life Cycle Stages; Light; Malaria; Methods; Modeling; Modification; Multi-Drug Resistance; Mutagenicity Tests; Mutagens; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Public Health; RNA-Directed DNA Polymerase; Research; Testing; Therapeutic; Therapeutic Index; Toxic effect; Tumor Initiators; Viral; Virus; Work; carcinogenicity; compliance behavior; concept; follow-up; halofantrine; indexing; inhibitor/antagonist; novel; phenanthrene; preclinical study; scaffold; small molecule; success; therapeutic target

DESCRIPTION (provided by applicant): Our studies on novel small molecules inhibitors of HIV integrase have led to the identification of new potent phenanthrene diketoacid (DKA) HIV integrase inhibitors that also inhibit HIV replication in cell culture, with a selectivity index up to 10. In light of the need for more effective and less toxic anti- HIV drugs, these results appear promising and warrant follow-up optimization and preclinical studies. However, since phenanthrenes are polyaromatic hydrocarbons (PAHs) with potential carcinogenicity we propose to investigate these novel phenanthrene diketoacids for carcinogenicity potential. Our hypothesis going forward is that appropriate substitution with electron withdrawing groups can minimize mutagenicity and produce useful anti-HIV agents. This is supported by the example of the new anti-malarial drug halofantrine, a substituted phenanthrene that is effective against multidrug resistant malaria, and is neither mutagenic nor teratogenic. We thus believe that appropriate substitution of our HIV integrase inhibitory phenanthrene DKAs will make them non-mutagenic and non-carcinogenic. Thus the specific aims of this proposal are: 1) to synthesize and test the IN inhibitory activity of new phenanthrene diketoacids with multiple electron withdrawing substituents and 2) to determine the carcinogenicity potential of the phenanthrene DKAs synthesized in Specific Aim 1. We will use the Ames test for in vitro carcinogenicity testing. The success of this project will provide vital information to decide whether or not to go ahead with optimization of the potent phenanthrene DKA HIV integrase inhibitors that we discovered recently and shown to selectively inhibit HIV replication in human peripheral blood mononuclear cells. If this approach to reducing carcinogenicity is successful it will not only provide a means of eliminating carcinogenicity of the phenanthrene DKAs, but may also provide a general method for reducing the carcinogenicity of PAH containing drugs. PUBLIC HEALTH RELEVANCE: This project is aimed at investigating whether or not a novel class of potent phenanthrene diketo acid HIV integrase inhibitors that have been shown to suppress HIV viral replication in cell culture, are carcinogenic. The results of the research will determine whether to carry on with further work on optimizing this class of new anti-HIV agents towards AIDS therapeutics development.

描述（由申请人提供）：我们对HIV整合酶的新型小分子抑制剂的研究已经鉴定出新型强效菲二酮酸（DKA）HIV整合酶抑制剂，其也抑制细胞培养物中的HIV复制，选择性指数高达10。鉴于对更有效和毒性更低的抗HIV药物的需求，这些结果看起来很有希望，并保证后续优化和临床前研究。然而，由于菲是具有潜在致癌性的多环芳烃（PAH），我们建议调查这些新的菲二酮酸的致癌潜力。我们的假设是，适当的取代吸电子基团可以最大限度地减少致突变性，并产生有用的抗HIV药物。新的抗疟疾药物卤泛群的例子支持了这一点，卤泛群是一种取代的菲，对耐多药疟疾有效，既不诱变也不致畸。因此，我们相信，适当取代我们的HIV整合酶抑制菲DKA将使它们无致突变性和非致癌性。因此，本提案的具体目的是：1）合成并测试具有多个吸电子取代基的新菲二酮酸的IN抑制活性，以及2）确定在具体目的1中合成的菲DKA的致癌性潜力。我们将使用艾姆斯试验进行体外致癌性试验。该项目的成功将提供重要的信息，以决定是否继续优化我们最近发现并显示出选择性抑制人类外周血单核细胞中HIV复制的强效菲DKA HIV整合酶抑制剂。如果这种降低致癌性的方法是成功的，它将不仅提供一种消除菲DKA致癌性的方法，而且还可以提供一种降低含PAH药物致癌性的通用方法。 公共卫生关系：该项目的目的是调查是否有一类新的有效的菲二酮酸HIV整合酶抑制剂，已被证明可以抑制细胞培养中的HIV病毒复制，是致癌的。研究结果将决定是否继续进一步优化这类新的抗艾滋病毒药物，以开发艾滋病治疗药物。