5'-Esters of 2'-deoxyadenosine and 2-chloro-2'-deoxyadenosine with cell differentiation-provoking agents.
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Phenylacetic and retinoic acids are carboxyacidic cell differentiating agents displaying anticancer activities. We report on a new class of compounds including the 5'-esters of 2'-deoxyadenosine (dA) or 2-chloro-2'-deoxyadenosine (cladribine, 2CdA) and the aforementioned acids. The rationale behind the synthesis of these esters was that if they are hydrolyzed inside the lymphoid cells, either dA will be removed from the intracellular environment by deamination, or 2CdA will be phosphorylated and accumulated. In either case targetted delivery of the differentiating agent to the lymphoid cells may be envisaged. The said compounds were synthesized by the Mitsunobu procedure employing triphenylphosphine and azadicarboxylic acid esters, and their stability was tested against various esterases. Esters of dA and 2CdA with phenylacetic acids were found to be resistant to enzymatic hydrolysis, whereas those with retinoic acids were efficiently hydrolyzed by commercially available hepatic esterase as well as by esterases present in the blood plasma and in diluted human lymphocyte lysate. Susceptibility to enzymatic hydrolysis was found to be a prerequisite of cytotoxic and/or differentiating activity of these esters in leukemic cell lines.
- 1. Newmark, H.L. & Young, C.W. (1995) Butyrate and phenylacetate as differentiating agents: Practical problems and opportunities. J. Cell. Biochem. 22 (Suppl.), 247-253.
- 2. Liu, L., Shack, S., Stetler-Stevenson, W.G., Hudgins, W.R. & Samid, D. (1994) Differentiation of cultured human melanoma cells induced by the aromatic fatty acids phenylacetate and phenylbutyrate. J. Invest. Dermatol. 103, 335-340.
- 3. Rohwedel, J., Guan, K. & Wobus, A.M. (1999) Induction of cellular differentiation by retinoic acid in vitro. Cells Tissues Organs. 165, 190-202.
- 4. Hudgins, W.R., Shack., S., Myers, C.E. & Samid, D. (1995) Cytostatic activity of phenylacetate and derivatives against tumor cells. Correlation with lipophilicity and inhibition of protein prenylation. Biochem. Pharmacol. 50, 1273-1279.
- 5. Miller, W.H., Jr. (1998) The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer. 83, 1471-1482.
- 6. Gore, S.D., Samid, D. & Weng, L.J. (1997) Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin. Cancer Res. 3, 1755-1762.
- 7. Witzig, T.E., Timm, M., Stenson, M., Svingen, P.A. & Kaufmann, S.H. (2000) Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin. Cancer Res. 6, 681-692.
- 8. Huang, Y. & Waxman, S. (1998) Enhanced growth inhibition and differentiation of fluorodeoxyuridine-treated human colon carcinoma cells by phenylbutyrate. Clin. Cancer Res. 4, 2503-2509.
- 9. Lengfelder, E., Reichert, A., Schoch, C., Haase, D., Haferlach, T., Loffler, H., Staib, P., Heyll, A., Seifarth, W., Saussele, S., Fonatsch, C., Gassmann, W., Ludwig, W.D., Hochhaus, A., Beelen, D., Aul, C., Sauerland, M.C., Heinecke, A., Hehlmann, R., Wormann, B., Hiddemann, W. & Buchner, T. (2000) Double induction strategy including high dose cytarabine in combination with all-transretinoic acid: Effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia 14, 1362-1370.
- 10. Venditti, A., Tamburini, A., Buccisano, F., Scimo, M.T., Del Poeta, G., Maurillo, L., Cox, M.C., Abruzzese, E., Tribalto, M., Masi, M. & Amadori, S. (2000) A phase-II trial of all transretinoic acid and low-dose cytosine arabinoside for the treatment of high-risk myelodysplastic syndromes. Ann. Hematol. 79, 138-142.
- 11. Niitsu, N. & Honma, Y. (1999) Adenosine analogs as possible differentiation-inducing agents against acute myeloid leukemia. Leuk. Lymphoma 34, 261-271.
- 12. Eriksson, S., Arner, E., Spasokoukotskaja, T., Wang, L., Karlsson, A., Brosjo, O., Gunven, P., Juliusson, G. & Liljemark, J. (1994) Properties and levels of deoxynucleoside kinases in normal and tumor cells: Implications for chemotherapy. Adv. Enzyme Regul. 34, 13-25.
- 13. Siaw, M.F., Mitchell, B.S., Koller, C.A., Coleman, M.S. & Hutton, J.J. (1980) ATP depletion as a consequence of adenosine deaminase inhibition in man. Proc. Natl. Acad. Sci. U.S.A. 77, 6157-6161.
- 14. Liliemark, J. (1997) The clinical pharmacokinetics of cladribine. Clin. Pharmacokinet. 32, 120-131.
- 15. Mitsunobu, O. (1981) The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1-28.
- 16. Parang, K., Wiebe, L.I. & Knaus, E.E. (2000) Novel approaches for designing 5'-O-ester prodrugs of 3'-azido-2',3'-dideoxythymidine. Curr. Med. Chem. 7, 995-1039.
- 17. Aggarwal, S.K., Gogu, S.R., Rangan, S.R. & Agrawal, K.C. (1990) Synthesis and biological evaluation of prodrugs of zidovudine. J. Med. Chem. 33, 1505-1510.
- 18. Frankel, S.R., Eardley, A., Lauwers, G., Weiss, M. & Warrell, R.P., Jr. (1992) The retinoic acid syndrome in acute promyelocytic leukemia. Ann. Intern. Med. 117, 292-296.
- 19. Vahdat, L., Maslak, P., Miller, W.H., Jr., Eardley, A., Heller, G., Scheinberg, D.A. & Warrell, R.P., Jr. (1994) Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: Impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 84, 3843-3849.
- 20. Kini, A.R., Peterson, L.C., Tallman, M.S. & Lingen, M.W. (2001) Angiogenesis in acute promyelocytic leukemia: Induction by vascular endothelial growth factor and inhibition by all-trans-retinoic acid. Blood 97, 3919-3924.
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