Synthesis and biological activity of pyrazolo[3,4-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin

Sidney Hecht, R. Bruce Frye, Dieter Werner, Toshikazu Fukui, S. D. Hawrelak

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at ≤ 1 μg/ml. 4-Amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5′-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRN A to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylysine in a cell-free system. The copolymer consisting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4°C.

Original languageEnglish (US)
Pages (from-to)1005-1015
Number of pages11
JournalBiochemistry
Volume15
Issue number5
StatePublished - 1976
Externally publishedYes

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sangivamycin
pyrazolo(3,4-d)pyrimidine
Toyocamycin
Tubercidin
Pyrimidine Nucleotides
Pyrimidine Nucleosides
Bioactivity
Adenosine
Copolymers
Polyribonucleotide Nucleotidyltransferase
Micrococcus luteus
Uridine Monophosphate
Hydrogen Sulfide
Nitriles
Adenosine Deaminase
Polylysine
Cell-Free System
Bioassay
Diphosphates
Cytotoxins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Synthesis and biological activity of pyrazolo[3,4-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin. / Hecht, Sidney; Frye, R. Bruce; Werner, Dieter; Fukui, Toshikazu; Hawrelak, S. D.

In: Biochemistry, Vol. 15, No. 5, 1976, p. 1005-1015.

Research output: Contribution to journalArticle

Hecht, Sidney ; Frye, R. Bruce ; Werner, Dieter ; Fukui, Toshikazu ; Hawrelak, S. D. / Synthesis and biological activity of pyrazolo[3,4-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin. In: Biochemistry. 1976 ; Vol. 15, No. 5. pp. 1005-1015.
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abstract = "The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at ≤ 1 μg/ml. 4-Amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5′-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRN A to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylysine in a cell-free system. The copolymer consisting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4°C.",
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AU - Frye, R. Bruce

AU - Werner, Dieter

AU - Fukui, Toshikazu

AU - Hawrelak, S. D.

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AB - The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at ≤ 1 μg/ml. 4-Amino-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5′-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRN A to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylysine in a cell-free system. The copolymer consisting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4°C.

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