Inhibition of IMP Dehydrogenase by Mycophenolic Acid in Molt F4 Human Malignant Lymphoblasts

Abstract

SUMMARY. The effects of inhibition of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide de novo synthesis, on cell growth, cell viability, endogenous nucleotide concentrations and concentrations of extracellular nucleosides and bases were studied in Molt F4 human malignant lymphoblasts. Mycophenolic acid (MPA) was used as a specific inhibitor of the enzyme activity. IMPDH activity was maximally inhibited with O·5 J.lM MP A. After a 2 h exposure of the cells to 0·5 J.lM MPA, guanine nucleotides were depleted to approximately 50% of control values, whereas 5-phosphoribosyl-l-pyrophosphate levels increased to approximately 200%. Under these conditions, cytotoxicity became obvious after 24 h. Depletion of guanine nucleotides and cytotoxicity were prevented by addition of guanosine to MP A treatment. Daily supplements of guanosine were required to prevent MPA cytotoxicity during the entire incubation period of 72 h. We conclude that depletion of guanine nucleotides, induced by treatment with MPA, induces a severe and rapid cytotoxicity in Molt F4 cells.

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

“…These compounds are not particularly toxic in confluent monolayers (see Table 1), but inhibit cell proliferation (Allen et al, 1977; Balzarini et al, 1998; Crance et al, 2003; Stet et al, 1994). In these assays the cultures received treatment when started as sub-confluent monolayers.…”

An Efficient synthesis of Dimethoxyphthalides

“…4 These phthalides are valuable as they possess significant biological properties 5,6 and also are widely accepted synthons for the construction of various types of polycyclic systems 7 including isocoumarins, 8 anthraquinones, 9 anthracycline antibiotics, 10 lignans, 11 etc. The phthalides 1b and 1e, for example, are potential precursors of mycophenolic acid (MPA) 3, an important antiparasitic, 12 antineoplastic 13 and antiviral 14 agent, in a synthesis involving a stereospecific orthoester Claisen rearrangement. 15 Although a variety of approaches for the synthesis of phthalides 1a, 16 1b 17 and 2 16h have been reported involving mostly use of organometallics, 16d,h considerable attention to new approaches for building these systems is still being paid because of their impressive biological properties and versatility as synthetic intermediates.…”