CHIRAL UNFUSED HETEROPOLARENES ANTI HIV AGENTS

本工作的目标是合成抗HIV-1抗体 药物（i）是高活性的，（ii）显示最小的毒性，和 (iii)生物稳定性好。 设计了一种高活性的 分子是基于40所获得的初步结果 七个被极性取代的未稠合的杂聚芳族化合物 连锁集团 这组化合物的成员表现出非常 有希望的抗HIV-1活性和低毒性。 初步 检测数据以及核酸结合研究强烈 表明这类分子的抗HIV活性是 由于识别病毒RNA的特定结构特征， 例如发夹环中的凸出碱基。 这些新药将 与RNA表现出强的立体特异性结合（高活性） 并且与染色质中的DNA的相互作用最小（低毒性）。 与RNA立体特异性结合的分子将由以下组成： (i)一种扭曲的未稠合的芳族体系，其能够插入或 部分插入螺旋桨扭曲的RNA碱基对 和/或RNA发夹环中凸出的碱基，和（ii）手性 取代基能够与C2 '-OH基团强烈相互作用 在RNA沟中通过氢键和磷酸 通过静电相互作用的RNA。 合成 这项工作经过精心设计，能够迅速产生大量 结构差异很小的化合物。 一系列 外消旋化合物将首先由容易获得的 氨基酸的衍生物。 有希望的化合物，如确定的 通过HIV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 筛选。 这些测试将消除不活跃（或不太活跃） 立体异构体，并将导致更好地了解 药物-受体相互作用 同时， 生物学和生物物理学测试数据将由 组 将提交更有前途的化合物。为 体内筛选。体内活性的化合物将另外被 用3 H或14 C标记，以促进 毒性、器官分布和生物稳定性研究。 额外 将进行综合修改（理解 药物-受体相互作用）以改善所需的性质 在获得体内研究的反馈后，

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.