CHIRAL UNFUSED HETEROPOLARENES ANTI HIV AGENTS

拟议工作的目标是合成抗艾滋病毒-L (I)高活性，(Ii)毒性最小的药物，以及 (3)具有良好的生物稳定性。设计了一种高活性的 分子是基于与40个 七种极性取代的非稠杂多化合物 链式群组。这组化合物的成员表现出非常 L具有良好的抗艾滋病病毒活性和低毒作用。预赛 测试数据和强烈的核酸结合研究 提示这类分子的抗HIV活性是 由于识别了病毒RNA的特定结构特征 例如发夹圈中凸起的底座。拟议中的新药将 表现出与RNA强烈的立体特异性结合(高活性) 染色质中与DNA的相互作用最小(低毒)。 与RNA立体特异性结合的分子将由 (I)能够插层的扭曲的不稠环芳香体系或 部分插入螺旋桨缠绕的碱基对的RNA 和/或RNA发夹环中的凸起碱基，和(Ii)手性 能够与C2‘-OH基团强相互作用的取代基 在RNA沟槽中通过氢键和磷酸盐 通过静电相互作用的RNA基团。合成材料 工作经过精心设计，以迅速产生大量 结构差异非常小的化合物。一系列 外消旋化合物将首先从现成的 氨基酸的衍生物。已确定的有希望的化合物 通过艾滋病毒检测，核酸结合研究，.和分配 系数信息(由其他研究小组获得)，将 以对映体形式合成，并重新提交给 放映。这些测试将消除非活动(或较不活跃) 立体异构体，将导致更好地理解 药物-受体相互作用。同时，定量构效关系分析的研究 生物和生物物理测试数据将由该中心进行 一群人。更有希望的化合物将被提交。为 体内筛选。体内活性的化合物将另外 被这个合成基团标记为~3H或~(14)C以促进 毒性、器官分布和生物稳定性研究。其他内容 将(在理解的情况下)进行综合修改 药物-受体相互作用)以改善所需的特性 从体内研究获得反馈后的活性药物。

The objective of the proposed work is to synthesize anti-HIV-l drugs that (i) are highly active, (ii) show minimal toxicity, and (iii) have good biostability. The design of a highly active molecule is based on the preliminary results obtained with forty seven unfused heteropolyaromatic compounds substituted with polar chain groups. Members of this group of compounds show very promising anti-HIV-l activity and low toxicity. The preliminary test data together with nucleic acids binding studies strongly suggest that the anti-HIV activity of this class of molecules is due to recognition of specific structural features of viral RNA such as bulged bases in hairpin loops. The proposed new drugs will exhibit strong, stereospecific binding with the RNA (high activity) and minimal interaction with DNA in chromatin (low toxicity). Molecules which stereospecifically bind to RNA will be composed of (i) a twisted unfused aromatic system able to intercalate or partially intercalate with propeller-twisted base-pairs of RNA and/or bulged bases in RNA hairpin loops, and (ii) a chiral substituent able to interact strongly with both the C2'-OH group in the RNA groove through hydrogen bonding and with a phosphate group of the RNA through electrostatic interaction. The synthetic work has been carefully designed to generate rapidly a large number of compounds with very small structural differences. A series of racemic compounds will be prepared first from readily available derivatives of amino acids. The promising compounds, as determined by HIV-tests, nucleic acids binding studies,.and partition coefficients information (obtained by other research groups), will be synthesized in enantiomeric forms and resubmitted for the screenings. These tests will eliminate nonactive (or less active) stereoisomers and will result in a better understanding of the drug-receptor interaction. Simultaneously, QSAR analyses of the biological and biophysical test data will be conducted by this group. The more promising compounds will be submitted. for screening in vivo. Compounds active in vivo will additionally be labeled with 3H or 14C by this synthetic group to facilitate toxicity, organ distribution, and biostability studies. Additional synthetic modifications will be undertaken (with an understanding of the drug-receptor interaction) to improve desirable properties of the active drug after the feedback from in vivo studies is obtained.