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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。糖皮质激素诱导的淋巴细胞死亡是经典的细胞凋亡模型。在淋巴细胞恶性肿瘤的治疗中，糖皮质激素已达到主要地位。另一类类固醇，氧化类固醇，其在化学和生物学上与糖皮质激素不同，也诱导淋巴细胞死亡。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机制仍有待研究。我们最近发现了一种新的药物，核苷和类固醇酸的酯共轭物，它具有非常有效的抗淋巴瘤活性。进一步的研究还表明，该药物的生长抑制是通过细胞凋亡引起的细胞死亡。我们拟以该药物为先导，对其相关化合物进行系统的构效关系研究。合成提出了改变结构的类固醇和核苷部分。将通过平行合成技术生产类固醇、核苷及其缀合物的各种类似物。将对缀合物的抗肿瘤活性和生长抑制机制进行药理学评价。构效关系的研究，包括分子模拟，将产生一个更好的理解的共轭物的结构要求，并提供了一个合理的基础上开发的一类新的抗淋巴瘤药物。

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.