Enzyme Inhibitors as Potential Anticancer and Antiviral

a .蛋白激酶C项目：使用我们不断改进的固相合成方法生成新的dag -内酯化学文库，继续在各种潜在治疗重要性领域产生重要的先导化合物。最近发表了我们首个具有RasGRP专属选择性的C1域选择性dag -内酯的研究结果，以及我们能够刺激α -分泌酶活性的dag -内酯的研究结果。今年发现的另一种dag -内酯在体内被发现是一种非常有效的放射敏感剂，当与辐射结合使用时，它可以使前列腺特异性抗原（PSA）水平降至接近零。一些dag -内酯的大规模合成已经完成，用于体内研究，目前正在研究与IL-12结合后干扰素产量的增加。与这些发现平行，我们继续在分子水平上研究这些dag -内酯的作用，剖析两种化学上不同的羰基（sn-1和sn-2）与蛋白质或膜组分的相互作用。2005年底和2006年初发表了两篇关于这些问题的完整论文。一种新的含有芳基的dag内酯家族的合成最近得到了扩展。b . Zebularine [2(1H)-嘧啶核糖体]的临床进展在去年因恒河猴的意外毒性而终止，当血浆浓度达到25微摩尔时致命。这与啮齿动物（大鼠和小鼠）完全没有毒性形成鲜明对比，即使在高剂量下也是如此。规避药物毒性和提高低剂量斑马碱活性的努力有两个方向：(1)合成亲脂性的斑马碱前药，能够传递5'-单磷酸（ZMP），绕过代谢激活和降解。这是一家德国公司（海德堡制药公司）和南加州大学的共同努力。为此，与这两家机构签署了合作协议，以制备和测试第一个候选药物，以及(2)开发2'-脱氧西布拉林的前药，旨在递送2-脱氧西布拉林-5'-单磷酸（dZMP）。许多2'-脱氧西丙拉碱前药似乎起作用，但只有在添加胸腺嘧啶的情况下才有效。最有可能的是，产生的dZMP抑制了两种关键酶，脱氧胞苷脱氨酶和胸腺苷酸合成酶，这两种酶对于维持正常的胸腺嘧啶水平都是必不可少的。c .稳定的NAD类似物，β -亚甲基- tad的使用，在过去的几年里在LMC合成，用于单adp -核糖基化毒素（类似于白喉毒素）的高分辨率晶体结构，去年发表在《自然》杂志上。

A.Protein kinase C project: The generation of novel chemical libraries of DAG-lactones using our constantly improved solid-phase method of synthesis continues to yield important lead compounds in various areas of potential therapeutic importance. The results on our first C1 domain-selective DAG-lactone with exclusive selectivity for RasGRP were published recently, as well as our results on DAG-lactones capable of stimulating alpha-secretase activity. Another DAG-lactone discovered this year was found to function as a very effective radiosentizer in vivo causing prostate-specific antigen (PSA) levels to drop to near zero when administered in conjunction with radiation. Large-scale syntheses of some of DAG-lactones were completed for in vivo studies, which are now in progress to investigate the increase in interferon production in combination with IL-12. In parallel to these findings, we continue to investigate the action of these DAG-lactones at the molecular level dissecting the interaction of the two chemically different carbonyl groups (sn-1 and sn-2) with the protein or membrane components. Two full papers addressing these issues were published late in 2005 and in early 2006. The syntheses of a new family or DAG-lactones containing aryl groups have been recently expanded. B.The progression toward the clinic for Zebularine [2(1H)-pyrimidinone riboside] was brought to an end last year by an unforeseen toxicity in rhesus monkeys, which was lethal when plasma levels reached 25 micromolar. This is in total contrast to the complete lack of toxicity in rodents (rats and mice), even at high doses. Efforts to circumvent the drug's toxicity and to improve the activity of zebularine at lower doses have been channeled in two directions: (1) Synthesis of a lipophilic prodrug of zebularine capable of delivering the 5'-monophosphate (ZMP), and bypassing metabolic activation and degradation. This is a joint effort with a German company (Heidelberg Pharma) and the University of Southern California. To that effect a Collaboration Agreement was signed with these two institutions to prepare and test the first candidate, and (2) The development of pro-drugs of 2'-deoxyzebularine, which are intended to deliver 2-deoxyzebularine-5'-monophosphate (dZMP). A number of 2'-deoxyzebularine prodrugs appear to work but only in the presence of added thymidine. Most likely, the dZMP generated inhibits two key enzymes, deoxycytidine deaminase and thymidylate synthase, and both are essential in maintaining normal thymidine levels.C.The use of stable NAD analogue, beta-methylene-TAD, synthesized at the LMC in years past and used for the high-resolution crystal structure of a mono-ADP -ribosylating toxin (similar to diphteria toxin) was highlighted in a paper published in Nature last year.