DDR SUBPROJECT 1: SYNTHESIS AND EVALUATION OF NEW STEROID-NUCLEOSIDE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 糖皮质激素诱导的淋巴细胞死亡是一种经典的细胞凋亡模型。在淋巴细胞性恶性肿瘤的治疗中，糖皮质激素已占据主导地位。另一类类固醇，氧合类固醇，在化学和生物学上与糖皮质激素不同，也会导致淋巴样细胞死亡。尽管对这一主题进行了深入的研究，但这两类类固醇对淋巴系统的详细作用机制仍有待研究。我们最近发现了一种新的药物，一种核苷和类固醇酸的酯结合物，它具有非常强大的抗淋巴瘤活性。进一步的研究还表明，S的生长抑制作用是通过细胞凋亡来实现的。我们建议以该药为先导，对其相关化合物进行系统的构效关系研究。提出了用于改变甾体和核苷部分结构的合成方法。通过平行合成技术将生产各种类固醇、核苷及其结合物的类似物。这些结合物将接受抗肿瘤活性和生长抑制机制的药理学评估。构效关系研究，包括分子模拟，将使人们更好地理解结合物的结构要求，并为开发新型抗淋巴瘤药物提供合理的基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glucocorticoids evoked death of lymphoid cells is a classical model of apoptosis. In the treatment of lymphocytic malignancy, glucocorticoids have attained a mainstay status. Another class of steroids, oxysteroids, which are different chemically and biologically from the glucocorticoids, also induce lymphoid cell death. The detailed mechanisms of the two classes of steroids on the lymphoid system remain to be worked out despite intensive research on the subject. We have recently discovered a novel agent, an ester conjugate of a nucleoside and a steroid acid, which gave exceptionally potent anti-lymphoma activities. Further studies have also revealed that the agent¿s growth inhibition was through cell death by apoptosis. We are proposing to follow the lead of this drug, and carry out a systematic structure-activity relationship study of its related compounds. Syntheses are proposed for alteration of structures on both the steroid and nucleoside moieties. Various analogs of steroids, nucleosides and their conjugates will be produced through parallel synthetic techniques. The conjugates will be subjected to pharmacological evaluations for their anti-tumor activity and mechanism of growth inhibition. Structure-activity correlation studies, including molecular modeling, will yield a better understanding of the structural requirement of the conjugates and provide a rational basis for the development of a new class of anti-lymphoma agents.