LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS

描述：（改编自申请人摘要）。的总目标 这个延续项目是发现新的代理人， 卡氏肺孢子虫和刚地弓形虫， 病原体已知是发病率和死亡率的主要原因， 获得性免疫缺陷综合征（AIDS）患者及AIDS相关 复合物（ARC）。 更具体地说，该项目将侧重于设计 和三环二氨基嘧啶衍生物的合成， 预期不仅具有曲美蝶呤（TMQ）的高效力， 吡嗪肟（PTX）的有利结合选择性， 甲氧苄啶（TMP）和乙胺嘧啶（PM）对卡氏肺孢子虫和T.弓形虫 二氢叶酸还原酶（DHFR），与哺乳动物DHFR相反。 化合物 提出的合成包括六种一般类型的6/6和6/5稠合 二氨基嘧啶系统，重点放在最初 具有短桥（不超过两个原子）和3，4，5 三甲氧基取代（如TMQ和TMP）或2，5-二甲氧基取代 (as在PTX中）。 合成方案足够通用， 具有其他环取代基的同系物的制备， 实例卤素。 将评价目标化合物的能力 抑制卡氏肺孢子虫DHFR，T.弓形虫和哺乳动物（大鼠肝脏） 细胞，以及那些显示出有希望的选择性和效力的细胞将被 作为抑制剂或人DHFR和CCRF CEM人的生长测试 淋巴母细胞 适当时，还可以测试化合物的 抑制卡氏肺孢子虫和T.弓形虫在饲养层中的生长 大鼠肺成纤维细胞。 具有足够活性的化合物， 这些体外试验的选择性，以证明进一步的临床前试验 开发将被确定为扩大合成的候选者， 以便最终能够在体内药理学和毒理学上 在小鼠和其他动物中进行的研究。 体外 利用卡氏肺孢子虫（P. carinii）、T.弓形虫和大鼠肝脏DHFR，以及 将继续使用培养中的完整寄生虫进行测定 Sherry Queener博士合作， 药理学和毒理学，印第安纳州大学医学院。 的 将使用人DHFR和培养的人细胞进行体外测定， 在达纳法伯执行的一部分，申请人的其他目前 在抗叶酸领域的资助工作。

DESCRIPTION: (Adapted from Applicant's Abstract). The overall goal of this continuation project is the discovery of new agents against Pneumocystis carinii and Toxoplasma gondii, two of the opportunistic pathogens known to be major causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC). More specifically, the project will focus on the design and synthesis of di and tricyclic diaminopyrimidine derivatives that are expected to have not only the high potency of trimetrexate (TMQ) and piritrexim (PTX) but also the favorable binding selectivity of tremethoprim (TMP) and pyrimethamine (PM) for P. carinii and T. gondii dihydrofolate reductase (DHFR) as opposed to mammalian DHFR. Compounds proposed for synthesis include six general types of 6/6 and 6/5 fused diaminopyrimidine systems, with emphasis being placed initially on compounds with a short bridge (no more than two atoms) and either 3,4,5 trimethoxy substitution (as in TMQ and TMP) or 2,5 dimethoxy substitution (as in PTX). The synthetic schemes are general enough to allow preparation of congeners with other ring substituents, including for example halogens. Target compounds will be evaluated for the ability to inhibit DHFR from P. carinii, T. gondii, and mammalian (rat liver) cells, and those that show a promising selectivity and potency will be tested as inhibitors or human DHFR and the growth of CCRF CEM human lymphoblasts. Compounds may also be tested, when appropriate, for the ability to inhibit P. carinii and T. gondii growth in feeder cultures of rat lung fibroblasts. Compounds with sufficient activity and selectivity in these in vitro assays to justify further preclinical development will be identified as candidates for scaled up synthesis, so as to eventually enable in vivo pharmacological and toxicological studies in mice and other animals to be carried out. The in vitro studies using P. carinii, T. gondii, and rat liver DHFR, as well as the assays using intact parasites in culture, will continue to be done collaboratively with Dr. Sherry Queener, of the Department of Pharmacology & Toxicology, Indiana University School of Medicine. The in vitro assays using human DHFR and human cells in culture will be performed at the Dana Farber as part of the applicant's other currently funded work in the antifolate area.