The Chemistry of Mycophenolic Acid - Synthesis and Modifications Towards Desired Biological Activity

Abstract

Mycophenolic acid (MPA) is a basis for the immunosuppressive drugs used in clinic against rejection in solid organs transplantations. Since its physiological activity is very promising, numerous studies have been performed to establish mechanism of action, structure - activity relationship (SAR), synthesis of MPA derivatives to improve or extent its clinical use to anticancer one, especially. The reported methods for preparation of MPA analogues have been achieved by semi-synthetic approaches or total synthesis and accomplished by in vitro or / and in vivo evaluations. In this review we would like to bring together chemical aspects of these compounds and their implementations within biological activity, their synthesis and structural modifications referred to the structure-activity relationship (SAR).

Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

“…They provided some derivatives indicating significant activity if comparison with parent MPA, which is in good agreement with molecular modeling studies 30,32,35 . Iwaszkiewicz-Grzes et al 39 synthesized amino acids derivatives of MPA 17 and 18 (Scheme 3).…”

“…As a result, new compounds are designed to evaluate their potential activity. It includes structural modifications of known IMPDH inhibitors and investigations of new substances, which were synthetically obtained or isolated from natural sources [30][31][32]35,36 .…”

“…In literature we can find a lot of new analogs, unfortunately only a few of them exhibit interesting activity 3,35,36 . Moreover, immunosuppressive agents cause side effect like dose-limiting gastrointestinal (GI) toxicity upon MMF or MPA oral administration.…”

Modifications of total synthesis of mycophenolic acid

“…As a result, numerous MPA modifications together with their biological evaluations were reported. [7][8][9][10][11][12][13][14][15][16][17][18] Although MPA is produced in industrial scale via fermentation processes, 19 its price for laboratory scale is still high. In the chemical literature are described attempts of total synthetic MPA from commercially available substrates.…”

Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents

“…This mechanism allows MPA 1 to decrease proliferation of lymphocytes. Hence, sodium mycophenolate [MPS, Myfortic (Novartis, Basel, Switzerland)] and MPA prodrug: mycophenolate mofetil [2-morpholinoethyl, MMF, CellCept (Roche, Basel, Switzerland)] are widely used in the clinic as immunosuppresants [1][2][3][4][5][6][7][8][9][10] in the prevention of allograft rejection and treatment of autoimmune diseases. However, adverse effects related to the treatment with MPA-based drugs, such as diarrhea, leukopenia, sepsis and vomiting, are the barrier to the administration of higher doses and more effective treatment.…”