Synthesis and cytokine modulation properties of pyrrolo[2,3-d]-4-pyrimidone nucleosides

A series of pyrrolo[2,3-d]pyrimidone nucleosides were synthesized and evalu ated for their ability to enhance Type 2 cytokines and to suppress Type 1 c ytokines in human T cells activated in vitro. Compounds 16b, 16c, 16d, 18c, and 19b induced substantial enhancement of IL-4 (a Type 2 cytokine) levels while three compounds (16b, 16c, and 16f) showed significant suppression o f IFN gamma (a Type 1 cytokine) levels. The results revealed a strict struc tural requirement for the nucleoside-mediated enhancement of IL-4. Modifica tions of the ribofuranose moiety of the nucleosides either abolished or dra matically reduced the activity. Both the 5'-hydroxy and 5-carboxamidine are crucial for the activity. Of the few nucleoside analogues that demonstrate d enhancement on Type 2 cytokine production, 7-(beta-D-ribofuranosyl)pyrrol o[2,3-d]-4-pyrimidone-5-carboxamidine (16c) showed a dramatic enhancement ( >200%) of IL-4 levels and a significant enhancement (36%) of IL-5 levels. M oreover, this compound showed substantial suppression of the Type 1 cytokin es, IFN gamma (42%), IL-2 (54%), and TNF alpha (55%). Similarly, compound 1 6b showed a substantial enhancement of IL-4 (46%) and suppression of IL-2 ( 35%), IFN gamma (30%), and TNF alpha (26%). To our knowledge, these are the first nucleoside analogues that induce a Type 2 cytokine bias in T cells. The cytokine modulation property of 16c and 16b merits the therapeutic eval uation of these compounds in treating diseases in which immunopathology is associated with polarized Type 1 cytokine responses.