Synthesis, Cytotoxicity, and Antiviral Activity of Some Acyclic Analogues of the Pyrrolo[2,3-d]pyrimidine Nucleoside Antibiotics Tubercidin, Toyocamycin, and Sangivamycin

Pranab K. Gupta, Sylvia Daunert, M. Reza Nassiri, Linda L. Wotring, John C. Drach, Leroy B. Townsend

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin and the seco nucleosides of tubercidin, toyocamycin, and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]-pyrimidine (1) with 1,3-bis(benzyloxy)-2-propoxymethyl chloride (2) afforded compound 3, which without isolation was debrominated to obtain 4-amino-5-cyano-7-[[1,3-bis(benzyloxy)-2-propoxy]methyl]pyrrolo[2,3-d]pyrimidine (4). Although catalytic hydrogenolysis failed, the benzyl ether functionalities of 4 were successfully cleaved by boron trichloride to afford 4-amino-5-cyano-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine (6). Conventional functional group transformation of the cyano group of 6 provided a number of novel 5-substituted derivatives. Tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were treated separately with sodium metaperiodate and then with sodium borohydride to afford the 2′,3′-seco derivatives 9a-c, respectively. The acyclic nucleoside 4-chloro-2-(methylthio)-7-[[1,3-bis(benzyloxy)-2-propoxy]methyl]pyrrolo[2,3-d] pyrimidine (10) was aminated, desulfurized with Raney Ni, and then debenzylated to provide the tubercidin analogue 11. Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed that although the parent compounds tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were very potent growth inhibitors, the acyclic derivatives 6, 7a-c, and 9a-c had only slight growth-inhibitory activity. Evaluation of compounds 6, 7a, 7b, 7c, 9a, 9b, 9c, 11 for cytotoxicity and activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the carboxamide (7a) and the thioamide (7c) were active. Compound 7c was the more potent of the two, inhibiting HCMV but not HSV-1 at concentrations producing little cytotoxicity.

Original languageEnglish (US)
Pages (from-to)402-408
Number of pages7
JournalJournal of Medicinal Chemistry
Volume32
Issue number2
DOIs
StatePublished - Feb 1 1989
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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