Arthur J. Spiess

Synthesis of fluorinated derivatives of methionine and 5′-deoxy-5′-(methylthio)-adenosine using the mccarthy transformation of sulfoxides to α-fluoro thioethers

Abstract Treatment of N-acetylmethionine sulfoxide methyl ester with diethylamino- sulfur trifluoride (DAST) or dimethylaminosulfur trifluoride (meDAST) yielded N-acetyl-S-(monofluoromethyl)homocysteine methyl ester as the sole fluorinated product. In contrast, treatment of 2′,3′-di-O-acetyl-5′-(methylthio)adenosine sulfoxide with DAST or meDAST unexpectedly produced three novel fluorinated products.

Improved Synthesis of β-D-6-Methylpurine Riboside and Antitumor Effects of the β-D- and α-D-Anomers

6-Methylpurine-β-D-riboside (β-D-MPR) has been synthesized by coupling 6-methylpurine and 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribose using conditions that produce the β-D-anomer exclusively. The in vitro antitumor effects of β-D-MPR and 6-methyl-purine-α-D-riboside (α-D-MPR) in five human tumor cell lines showed that β-D-MPR was highly active (IC50 values ranging from 6 to 34 nM). α-D-MPR, although less active than β-D-MPR, also exhibited significant antitumor effects (IC50 values ranging from 1.47 to 4.83 μM).

Novel Trypanocidal Analogs of 5′-(Methylthio)-Adenosine

ABSTRACT The purine nucleoside 5′-deoxy-5′-(hydroxyethylthio)-adenosine (HETA) is an analog of the polyamine pathway metabolite 5′-deoxy-5′-(methylthio)-adenosine (MTA). HETA is a lead structure for the ongoing development of selectively targeted trypanocidal agents. Thirteen novel HETA analogs were synthesized and examined for their in vitro trypanocidal activities against bloodstream forms of Trypanosoma brucei brucei LAB 110 EATRO and at least one drug-resistant Trypanosoma brucei rhodesiense clinical isolate. New compounds were also assessed in a cell-free assay for their activities as substrates of trypanosome MTA phosphorylase. The most potent analog in this group was 5′-deoxy-5′-(hydroxyethylthio)-tubercidin, whose in vitro cytotoxicity (50% inhibitory concentration [IC50], 10 nM) is 45 times greater than that of HETA (IC50, 450 nM) against pentamidine-resistant clinical isolate KETRI 269. Structure-activity analyses indicate that the enzymatic cleavage of HETA analogs by trypanosome MTA phosphorylase is not an absolute requirement for trypanocidal activity. This suggests that additional biochemical mechanisms are associated with the trypanocidal effects of HETA and its analogs.

Purine 2′, 3′-acyclonucleosides: Improved synthesis and antiparasitic actimity

Abstract Synthesis of purine 2′,3′-acyclonucleosides has been improved by using methanol as solvent for sequential oxidation/reduction reactions on periodate- and borohydride-bound resins. Several O-acetylated derivatives of acyclic analogs prepared by this procedure have significant antitrypanosomal activity in vitro .

Synthesis and Biological Effects of 5′-Deoxy-5′-(Cyclo-Propylmethylthio)Adenosine

Abstract A novel synthesis of the nucleoside analog, 5′-deoxy-5′-(cyclopropylmethylthio)adenosine (CPMTA, 1) has been developed. CPMTA is a closely related structural analog of 5′-deoxy-5′-(isobutylthio)-adenosine (SIBA, 2), which has been widely studied and shown to exert a multitude of biological effects. The in vitro and in vivo antitumor (L1210 leukemia) activity of CPMTA has been found to be comparable to that of SIBA, whereas its in vitro antiviral (HSV and VSV) activity is diminished. These agents are being developed as inhibitors of methylation and/or polyamine synthesis.