Synthesis and Modeling Studies with Monocyclic Analogues of Mycophenolic Acid

Abstract

Two stepwise procedures, developed for the introduction of the (E)-4-methyl-4-hexenoic acid side chain of mycophenolic acid, were used in the synthesis of monocyclic mycophenolic acid analogues 2a-i. The derivatives with a methyl group or hydrogen at C-4 and lacking the lactone moiety were much less cytotoxic than mycophenolic acid. The monocyclic analogues with a C-4 chloro group did show some activity, albeit much less than mycophenolic acid. The observed differences in potency are rationalized by semiempirical calculations of intramolecular H-bonds.

Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

“…A more extensive discussion of structureactivity relationships was given in 1996. 137 Monocyclic analogues of MPA have been investigated; they are essentially benzenoid structures lacking the lactone ring. Of nine structures, 45 with R ) OCH 3 and 45 with R ) CH 3 showed some activity against L-1210 leukemia cells in tissue culture.…”

Nuclear Magnetic Resonance and Molecular Modeling Study on Mycophenolic Acid: Implications for Binding to Inosine Monophosphate Dehydrogenase

“…The representation of the overlaid conformations on Figure shows that this arrangement of the two molecules could also rationalize the role of the phenolic hydroxyl of MPA which is placed close enough to the C2‘-OH of the ribose (O−O distance: 2.95 Å) and/or the positively charged N1 (N−O distance: 2.29 Å) to hydrogen bond with a suitably positioned residue in the active site which originally stabilizes NAD + through H-bonding or electrostatic interaction. However, this interaction requires the disturbance of the intramolecular H-bonding of the phenol with the lactone carbonyl to take place as we have previously proposed 5 Superposition of 2d and NAD + . 4 rms Values for Least-Squares Fit of 2d and NAD + as a Function of the Altered Dihedral Angles of NAD + Derived from Glutathone Reductase no.…”

“…However, this interaction requires the disturbance of the intramolecular Hbonding of the phenol with the lactone carbonyl to take place as we have previously proposed. 20 Ligands that bind to the same active site of a particular enzyme are expected to possess comparable electrostatic properties which enable them to comply with the necessity of electrostatic complementarity with the enzyme-binding site. Accordingly, we examined the molecular electrostatic potentials (MEP) generated by 2d and NAD + at 1.1 x vdW radii visualized by potential color method on dot surfaces (Figures 6 and 7).…”

Pyrolysis of Calcium Salt of Alkoxybenzoic Acids Fails to Produce Diarylketones: An Unusual Observation

“…All the compounds are known compounds and the spectroscopic data [infrared (IR), 1 H NMR, and 13 C NMR] of the synthesized compounds are in good agreement with the literature reports. [4][5][6][7][8][9][10][11][12][13][14][15][16] Thin-layer chromatography (TLC) of the synthesized compounds was also identical with the authenticated samples. 55.2, 113.9, 119.3, 121.8, 129.2, 131.3, 159.4, 166.8)].…”