Novel S-adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis

Barker, et al. AAC

Supporting Information

Synthesis of MDL 73811 and Analogs.

Synthesis of MDL73811 was described elsewhere (1) – Supplemental Information.

Schemes 1 and 2 illustrate the synthetic methods used to construct the derivatives of MDL 73811 with desired changes on either the ribose or purine moieties. In Scheme 1, the purine nucleoside 2 (a-c) was treated with either mesyl chloride or tosyl chloride in pyridine at 0oC. Displacement by (Z)-tert-butyl 4-(methylamino)but-2-enylcarbamate in DMSO in the presence of triethyl amine formed compound 3, which, in 3a and 3b,was subjected to deprotection of the N6-benzoyl group by using ammonia in methanol. Final deprotection of the Boc group with HCl in ethyl acetate produced compound 4. In Scheme 2, the starting nucleoside 5was reacted with thionyl chloride and pyridine in acetonitrile at 0oC, followed by treatment with ammonium hydroxide in methanol. The resulting 5’-chloro-adenosine derivatives were reacted with methylamine in ethanol at elevated temperature to produce 6. N-alkylation of 6 with (Z)-tert-butyl 4-chlorobut-2-enylcarbamate in the presence of potassium carbonate and a catalytic amount of sodium iodide in DMSO, followed by deprotection of the Boc group with HCl in either methanol or dioxane gave the desired compound 7(2)

References:

1.Willert, E. K., R. Fitzpatrick, and M. A. Phillips. 2007. Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog. Proc Natl Acad Sci U S A 104:8275-8280.

2.Casara, P., P. Marchal, J. Wagner, and C. Danzin. 1989. 5'-{[(Z)-4-Amino-2-butenyl]methylamino}-5'-deoxyadenosine: a potent enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase from Escherichia coli. J Am Chem Soc 111:9111-9113.

3.2a was prepared from 9--D-arabinofuranosyladenine based on a literature procedure: Kawasaki, A. M., M. D. Casper, S. M. Freier, E. A. Lesnik, M. C. Zounes, L. L. Cummins, C. Gonzalez, and P. D. Cook. 1993. Uniformly modified 2'-deoxy-2'-fluoro-phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J Med Chem 36:831-841.

4.2b was prepared from 9-(2-Deoxy-2-fluoro--D-arabinofuranosyl)adenine based on literature procedures: a) Pankiewicz, K. W., J. Krzeminski, L. A. Ciszewski, W.-Y. Ren, and K. A. Watanabe. 1993. A synthesis of 9-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)adenine and -hypoxanthine. An effect of C3'-endo to C2'-endo conformational shift on the reaction course of 2'-hydroxyl group with DAST. J Org Chem 57:553-559. B) Krainer, E., F. Naider, and J. Becker. 1993. A new method for the detritylation of alcohols bearing other reducible and acid-hydrolyzable functionalities. Tetrahedron Lett 34:1713-1716.

5.2c was prepared from2-chloro-9--D-arabinofuranosyladenine by reaction with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid in acetone and DMF.