Carcinogenicity Testing of Novel Phenanthrene Diketoacid Anti-HIV Agents

描述（由申请人提供）：我们对新型HIV整合酶小分子抑制剂的研究导致鉴定出新的有效的菲二酮酸（DKA） HIV整合酶抑制剂，这些抑制剂也可以抑制细胞培养中的HIV复制，选择性指数高达10。鉴于需要更有效和毒性更小的抗HIV药物，这些结果看起来很有希望，值得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芳烃（PAHs），我们建议研究这些新的菲二酮酸的致癌性。我们下一步的假设是，适当的吸电子基团替代可以最大限度地减少诱变性，并产生有用的抗hiv药物。新的抗疟疾药物卤蝶碱的例子支持了这一点，卤蝶碱是一种取代的菲，对耐多药疟疾有效，而且既不致突变也不致畸。因此，我们相信适当的替代我们的HIV整合酶抑制菲dka将使它们非致突变和非致癌性。因此，本课题的具体目的是：1)合成并测试具有多个吸电子取代基的新型菲二酮酸的IN抑制活性；2)确定在specific Aim 1中合成的菲dka的致癌性。我们将使用Ames试验进行体外致癌性试验。该项目的成功将提供重要信息，以决定是否继续优化我们最近发现的有效的菲DKA HIV整合酶抑制剂，并显示出选择性地抑制人类外周血单个核细胞中的HIV复制。如果这种降低致癌性的方法成功，将不仅为消除菲dka的致癌性提供一种手段，而且可能为降低含多环芳烃药物的致癌性提供一种通用的方法。

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.