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

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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.