3-(1-deoxyribofuranosyl)benzamide and Leukemia

Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.

Topics: Adenine Nucleotides; Antineoplastic Agents; Cell Differentiation; Diphosphonates; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Isoenzymes; K562 Cells; Leukemia; Mycophenolic Acid; Structure-Activity Relationship

Benzamide riboside (BR) is a novel anticancer agent exhibiting pronounced activity against several human tumor cells, however, little is known about its biotransformation. To analyze for BR and its metabolites, livers of Wistar and mutant TR- rats were perfused with BR in a single pass system. In bile, native BR and its deamination product, benzene carboxylic acid riboside (BR-COOH) was quantified by HPLC. Total excretion of BR and BR-COOH into bile of Wistar rats was low (< 0.2%) whereas cumulative efflux of BR and its metabolite BR-COOH was high, representing 79% and 1.6% of infused BR, respectively. Biliary excretion of BR and BR-COOH in TR- rats, deficient in canalicular multispecific organic anion transporter, a membrane protein identical to MRP2 in tumor cells, was only slightly lower than in Wistar rats, indicating that BR and BR-COOH are non-substrates of MRP2. Experiments using rat hepatocytes incubated with BR did show a linear uptake of BR and a subsequent metabolism to BR-COOH that was largely excreted into the cellular supernatant. Examination of the cytotoxic activity against the human HL60 and K562 leukemia cells in a clonogenic assay demonstrated an IC50 of 619 microM and 1013 microM for BR-COOH compared to the IC50 of 0.21 microM and 0.46 microM for BR, suggesting the inertness of the metabolite. In summary, we found that deamination of BR to BR-COOH is the main metabolic pathway in rat liver. BR-COOH formation should also be considered in human liver during cancer therapy.

Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; Humans; IMP Dehydrogenase; In Vitro Techniques; Leukemia; Liver; Male; Nucleosides; Rats; Rats, Mutant Strains; Rats, Wistar; Tumor Cells, Cultured