Improved synthesis of 2'-deoxyformycin A and studies of its in vitro activity against mouse lymphoma of T-cell origin.

Abstract

7-Amino-3-(2'-deoxy-beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine (2'-deoxyformycin A) was synthesized from formycin A by a sequence consisting of (i) 3',5'-cyclosilylation with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, (ii) 2'-acylation with phenoxythiocarbonyl chloride and 4-(N,N-dimethylamino)pyridine, (iii) N-trimethylsilylation with hexamethyldisilazane, (iv) reduction of the 2'-O-phenoxythiocarbonyl group with tri-n-butyltin hydride, and (v) desilylation with tetra-n-butylammonium fluoride. 2'-Deoxyformycin A was a potent inhibitor of the in vitro growth of S49 lymphoma, a murine tumor of T-cell origin. The IC50 of 2'-deoxyformycin A against S49 cells was 10-15 microM, whereas that of 2'-deoxyadenosine (dAdo) under the same conditions (72-h incubation in medium containing heat-inactivated horse serum) was 180 microM. In the presence of 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to block intracellular adenosine deaminase (ADA) activity, 2'-deoxyformycin A and dAdo both gave IC50's of 5-10 microM. When assayed against a mutant S49 subline lacking adenosine kinase (AK) or a subline with a combined deletion of AK and deoxycytidine kinase (dCK), 2'-deoxyformycin A in combination with 10 microM EHNA was inactive at concentrations of up to 50 microM. Similar lack of activity against kinase-deficient cells was shown by formycin A. Thus, phosphorylation of 2'-deoxyformycin A appears to be required for biological activity and is probably catalyzed by AK rather than dCK. 2'-Deoxyformycin A and related 2'-deoxyribo-C-nucleoside analogues of the purine type may be of interest as potential T-cell specific cytotoxic agents.

• Authors: A Rosowsky, V C Solan, L J Gudas
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 28 Issue 8 Pg. 1096-9 (Aug 1985) ISSN: 0022-2623 [Print] United States
• PMID: 3874961 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Deoxyadenosines
• Formycins
• formycin
• 2'-deoxyformycin A
• Adenosine Kinase

Topics

• Adenosine Kinase (metabolism)
• Animals
• Antibiotics, Antineoplastic (chemical synthesis)
• Cells, Cultured
• Deoxyadenosines (pharmacology)
• Formycins (chemical synthesis, metabolism, pharmacology)
• Lymphoma (drug therapy)
• Mice
• T-Lymphocytes