Synthesis and Biological Evaluation of Some Phosphate Triester Derivatives of the Anti-cancer Drug AraC

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 1989 Sep 25

PMID 2798090

Citations 4

Authors

B C Jones

C McGuigan

P A Riley

Affiliations

Soon will be listed here.

Abstract

A number of novel phosphate triester derivatives of the anti-cancer nucleoside analogue araC have been prepared by a rapid 2-step procedure, not necessitating prior sugar protection. Spectroscopic and lipophilicity data have been collected on these compounds. An in vitro assay indicated inhibition of thymidine incorporation by mammalian epithelial cells, by each of these compounds, in the range 3-300 microM. Moreover, the degree of inhibition showed a close correlation to chemical structure; in particular, there was a clear relationship between inhibition of thymidine incorporation and log(P). These results are consistent with cellular penetration by the intact phosphate triesters and intracellular action by an unspecified mechanism. Triethyl phosphate is inactive under the conditions of the test.

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References

Hamamura E, Prystasz M, Verheyden J, Moffatt J . Reactions of 2-acyloxyisobutyryl halides with nucleosides. Synthesis and biological evaluation of some 3"-acyl and 3',5'-diacyl derivatives of 1-beta-D-arabinofuranosylcytosine. J Med Chem. 1976; 19(5):667-74. DOI: 10.1021/jm00227a018. View

Lauer S, Pinkel D, Buchanan G, SARTAIN P, CORNET J, Krance R . Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia. Cancer. 1987; 60(10):2366-71. DOI: 10.1002/1097-0142(19871115)60:10<2366::aid-cncr2820601003>3.0.co;2-u. View

Lichtenstein J, Barner H, COHEN S . The metabolism of exogenously supplied nucleotides by Escherichia coli. J Biol Chem. 1960; 235:457-65. View

Hunston R, Jones A, McGuigan C, Walker R, Balzarini J, De Clercq E . Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine. J Med Chem. 1984; 27(4):440-4. DOI: 10.1021/jm00370a005. View

COHEN S, Flaks J, Barner H, Loeb M, Lichtenstein J . THE MODE OF ACTION OF 5-FLUOROURACIL AND ITS DERIVATIVES. Proc Natl Acad Sci U S A. 1958; 44(10):1004-12. PMC: 528686. DOI: 10.1073/pnas.44.10.1004. View

Farquhar D, Kuttesch N, Wilkerson M, Winkler T . Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'-phosphate. J Med Chem. 1983; 26(8):1153-8. DOI: 10.1021/jm00362a013. View

Keating M, McCredie K, Bodey G, Smith T, GEHAN E, Freireich E . Improved prospects for long-term survival in adults with acute myelogenous leukemia. JAMA. 1982; 248(19):2481-6. View

Prusoff W, Goz B . Potential mechanisms of action of antiviral agents. Fed Proc. 1973; 32(6):1679-87. View

Ryu E, Ross R, Matsushita T, MacCoss M, Hong C, West C . Phospholipid-nucleoside conjugates. 3. Syntheses and preliminary biological evaluation of 1-beta-D-arabinofuranosylcytosine 5'-monophosphate-L-1,2-dipalmitin and selected 1-beta-D-arabinofuranosylcytosine 5-diphosphate-L-1,2-diacylglycerols. J Med Chem. 1982; 25(11):1322-9. DOI: 10.1021/jm00353a010. View

10.

Furman P, Fyfe J, St Clair M, Weinhold K, Rideout J, Freeman G . Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986; 83(21):8333-7. PMC: 386922. DOI: 10.1073/pnas.83.21.8333. View

11.

Chawla R, FREED J, Hampton A . Bis(m-nitrophenyl) and bis(p-nitrophenyl) esters and the phosphorodiamidate of thymidine 5'-phosphate as potential sources of intracellular thymidine 5'-phosphate in mouse cells in culture. J Med Chem. 1984; 27(12):1733-6. DOI: 10.1021/jm00378a036. View

12.

Neil G, WILEY P, Manak R, Moxley T . Antitumor effect of 1-beta-D-arabinofuranosylcytosine 5'-adamantoate (NSC 117614) in L1210 leukemic mice. Cancer Res. 1970; 30(4):1047-54. View

13.

Bloch A, Robins M, McCarthy Jr J . The role of the 5'-hydroxyl group of adenosine in determining substrate specificity for adenosine deaminase. J Med Chem. 1967; 10(5):908-12. DOI: 10.1021/jm00317a034. View

14.

Bapat A, Zarow C, Danenberg P . Human leukemic cells resistant to 5-fluoro-2'-deoxyuridine contain a thymidylate synthetase with lower affinity for nucleotides. J Biol Chem. 1983; 258(7):4130-6. View

15.

Momparler R . A model for the chemotherapy of acute leukemia with 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1974; 34(8):1775-87. View

16.

Uchida K, Kreis W . Studies on drug resistance. I. Distribution of l-beta-D-arabinofuranosylcytosine, cytidine and deoxycytidine in mice bearing ara-C-sensitive and-resistant P815 neoplasms. Biochem Pharmacol. 1969; 18(5):1115-28. DOI: 10.1016/0006-2952(69)90115-4. View

17.

HANZE A . Nucleic acids. IV. The catalytic reduction of pyrimidine nucleosides (human liver deaminase inhibitors). J Am Chem Soc. 1967; 89(25):6720-5. DOI: 10.1021/ja01001a057. View

18.

LePAGE G . BASIC BIOCHEMICAL EFFECTS AND MECHANISM OF ACTION OF 6-THIOGUANINE. Cancer Res. 1963; 23:1202-6. View

19.

WECHTER W, Johnson M, Hall C, WARNER D, Berger A, Wenzel A . ara-Cytidine acylates. Use of drug design predictors in structure-activity relationship correlation. J Med Chem. 1975; 18(4):339-44. DOI: 10.1021/jm00238a003. View

20.

REICHARD P, SKOLD O, Klein G, Revesz L, MAGNUSSON P . Studies on resistance against 5-fluorouracil. I. Enzymes of the uracil pathway during development of resistance. Cancer Res. 1962; 22:235-43. View