Synthesis, cytotoxicity, and antiviral activity of some acyclic analogues of the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin, and sangivamycin.

摘要: A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3d-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin the seco nucleosides tubercidin, toyocamycin, were prepared tested for their biological activity. Treatment sodium salt 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]-pyrimidine with 1,3-bis(benzyloxy)-2-propoxymethyl chloride afforded compound 3, which without isolation was debrominated obtain 4-amino-5-cyano-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine. Although catalytic hydrogenolysis failed, benzyl ether functionalities 4 successfully cleaved by boron trichloride afford 4-amino-5-cyano-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidine. Conventional functional group transformation cyano 6 provided a novel 5-substituted derivatives. Tubercidin (8a), (8b), (8c) treated separately metaperiodate then borohydride 2',3'-seco 9a-c, respectively. The acyclic nucleoside 4-chloro-2-(methylthio)-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine aminated, desulfurized Raney Ni, debenzylated provide tubercidin analogue 11. Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed although parent compounds very potent growth inhibitors, 6, 7a-c, 9a-c had only slight growth-inhibitory Evaluation 7a, 7b, 7c, 9a, 9b, 9c, 11 cytoxicity activity human cytomegalovirus (HCMV) herpes simplex virus type 1 (HSV-1) revealed carboxamide (7a) thioamide (7c) active. Compound 7c more two, inhibiting HCMV but not HSV-1 at concentrations producing little cytotoxicity.