H. Jeanette Thomas

Adenosylhomocysteine hydrolase inhibitors: synthesis of 5'-deoxy-5'-(isobutylthio)-3-deazaadenosine and its effect on Rous sarcoma virus and Gross murine leukemia virus.

Abstract The synthesis of a new analog of adenosylhomocysteine (AdoHcy), 5′-deoxy-5′-(isobutylthio)-3-deazaadenosine, is described. The compound is a non-competitive inhibitor of AdoHcy hydrolase, with a K i of 0.4 mM, as compared to a K i of 3 μM for 3-deazaadenosine, a competitive inhibitor of the enzyme. 5′-Deoxy-5′-(isobutylthio)-3-deazaadenosine is not hydrolyzed by AdoHcy hydrolase. 5′-Deoxy-5′-(isobutylthio)-3-deazaadenosine when tested has a selective antiviral activity against Rous sarcoma virus in chick embryo cells, and against Gross murine leukemia virus in mouse embryo cells. Possible mechanisms of this anti-viral activity are discussed.

Synthesis and Biologic Activity of Purine 2′-Deoxy-2′-fluoro-ribonucleosides

Abstract The synthesis of 3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribofuranosyl bromide (8) and its reaction with 2,6-dichloropurine by fusion and with mercuric cyanide catalysis is described. The resulting 2,6-dichloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluor[ddot]-D-ribofuranosyl)purine (13) was converted to the 2-fluoroadenine (16), the 2-chloroadenine (17), 2,6-diaminopurine (12), and guanine (14) nucleosides by standard procedures. These nucleosides were cytotoxic to a number of cell lines in culture. The 2-haloadenine nucleosides 16 and 17 gave modest increases in lifespan when tested against the P388 leukemia in mice.

Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine

Aminopropyltransferases are essential enzymes that form polyamines in eukaryotic and most prokaryotic cells. Spermidine synthase (SpdS) is one of the most well‐studied enzymes in this biosynthetic pathway. The enzyme uses decarboxylated S‐adenosylmethionine and a short‐chain polyamine (putrescine) to make a medium‐chain polyamine (spermidine) and 5′‐deoxy‐5′‐methylthioadenosine as a byproduct. Here, we report a new spermidine synthase inhibitor, decarboxylated S‐adenosylhomocysteine (dcSAH). The inhibitor was synthesized, and dose‐dependent inhibition of human, Thermatoga maritima, and Plasmodium falciparum spermidine synthases, as well as functionally homologous human spermine synthase, was determined. The human SpdS/dcSAH complex structure was determined by X‐ray crystallography at 2.0 Å resolution and showed consistent active site positioning and coordination with previously known structures. Isothermal calorimetry binding assays confirmed inhibitor binding to human SpdS with Kd of 1.1 ± 0.3 μM in the absence of putrescine and 3.2 ± 0.1 μM in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.

Furanose–pyranose isomerization in a synthesis of 8-azapurine nucleosides

The four isomeric 9-ribosyl derivatives of 8-azahypoxanthine have been prepared from 6-chloro-9(2,3-O-isopropylidene-β-D-ribofuranosyl)purine by ring opening and re-closure reactions.

Synthesis of an Epoxide Derivative of Thymidine as a Potential Enzyme Inhibitor

Abstract Attempts to prepare I -[7,8-anhydro-2,5,6-trideoxy-α-L-lyxo-(and β-n-ribo)-octofuranosyl]thymine (10) by treatment of halohydrins 6–9 with sodium hydride in DMF or sodium methoxide in methanol gave mixtures of the epoxides 10 or 11 and the 3′,8′-anhydronucleoside 12. The structure of 12 was confirmed by oxidation to the cyclic ketone 14. The successful synthesis of 10 involved a Wittig reaction on the thymidine-5′-aldehyde 16 to give the unsaturated ketoacetate 18 which was reduced in two steps to the diacetate 20. The 7′-O-tosyl derivative 21 upon treatment with sodium methoxide in chloroform gave the pure epoxide 10 which was marginally toxic to L1210 cells in culture (I50=25 μM) and demonstrated borderline in vivo activity (24% ILS) against P388 murine leukemia.

The Synthesis of Coformycin from 5-Amino-1-β-D-ribofuranosylimidazole-4-carboxamide

Abstract A convenient synthesis of cotormycin from commercially available 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide is described.