DNA AS TARGET FOR ANTIPNEUMOCYSTIS CARINII AGENTS

DNA 作为抗卡氏肺孢子菌药物的靶标

• 批准号: 2076720
• 负责人: Isaac O. Donkor
• 金额: $ 10.53万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2076720
• 关键词: DNA footprinting; Pneumocystis carinii; Pneumocystis pneumonia; analog; antiprotozoal agents; drug design /synthesis /production; laboratory rat; pentamidine; pharmacokinetics; tissue /cell culture

DESCRIPTION: (Adapted from Applicant's Abstract). The long term goal of this AREA proposal is to elucidate the molecular target for the anti- Pneumocystis carinii activity of aromatic diamidines, and to use this knowledge to develop new chemotherapeutic agents. The short term goal of the proposal is to determine if the activity of the aromatic diamidines is mediated by sequence-selective binding to the minor groove of DNA. Pentamidine is one of the drugs of choice for treating Pneumocystis carinii pneumonia (PCP) which afflicts between 60 - 80% of AIDS patients in the U. S. Geometric isomers have been synthesized as semirigid congeners of pentamidine for investigating the mechanism of action of the drug. In vitro DNA-binding studies and footprinting studies showed that the cis isomer binds with higher affinity to DNA than does the trans isomer and that the binding affinity correlates with the in vitro anti-P. carinii activity. These compounds were, however, equipotent in an in vivo model of PCP. Based on these results it is hypothesized that: i) DNA is the molecular target for the anti-P. carinii activity of aromatic diamidines; and ii) the geometric isomers are subject to stereoselective pharmacokinetic processes resulting in greater in vivo exposure to the trans isomer and equipotent efficacy as compared to the cis isomer. These hypotheses will be tested by synthesizing compounds with varying binding affinities for DNA. The invitro and invivo anti-P. carinii activities will be determined. Pharmacokinetic studies will be carried out and the results analyzed to determine if there is a statistically significant correlation between in vitro DNA binding affinity, in vitro anti-P. carinni activity, and in vivo exposure and anti-P. carinii activity of the aromatic diamidines to establish DNA as their molecular target of action.

描述：（改编自申请人的摘要）。长期目标的 该领域的建议是阐明抗抗的分子靶标 芳族二氨酸的肺炎藻藻活性，并使用 知识以开发新的化学治疗剂。短期目标 该提案的内容是确定芳香族的活性是否 二氨酸是通过序列选择性结合与小凹槽介导的 DNA。五丹胺是治疗的首选药物之一 肺炎雄杆菌Carinii肺炎（PCP），遭受60-80％的折磨 美国几何异构体的艾滋病患者已合成为 五丹胺的半植物同源物研究了 药物的作用。体外DNA结合研究和足迹 研究表明，顺式异构体与DNA的亲和力高于 反式异构体和结合亲和力与 体外抗P。 Carinii活动。但是，这些化合物是 PCP体内模型中的等值。基于这些结果是 假设：i）DNA是抗P的分子靶标。 carinii 芳族二氨酸的活性； ii）几何异构体是 受到立体选择性药代动力学过程，导致 体内更大的体内暴露于跨异构体和等值效力为 与顺式异构体相比。这些假设将通过 具有不同结合亲和力的DNA的合成化合物。这 Invitro和Invivo Anti-P。将确定Carinii活动。 将进行药代动力学研究，并分析结果 确定是否存在统计学意义的相关性 体外DNA结合亲和力，体外抗P。 Carinni活动，和 体内暴露和抗P。芳族二氨酸的Carinii活性 建立DNA作为其分子作用靶标。

项目成果

Novel bisbenzamidines and bisbenzimidazolines as noncompetitive NMDA receptor antagonists.

新型双苯甲脒和双苯并咪唑啉作为非竞争性 NMDA 受体拮抗剂。

• DOI: 10.1016/s0960-894x(99)00184-5
• 发表时间: 1999
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Tao,B;Huang,TL;Sharma,TA;Reynolds,IJ;Donkor,IO
• 通讯作者: Donkor,IO