Mycophenolic acid synthesis

A P450-Hydrolase Fusion in Mycophenolic Acid Synthesis... 

Mycophenolate mofetil was approved by the FDA in 1995, and enteric-coated mycophenolic acid was approved in 2004. Both agents are considered to be adjunctive immunosuppressants. Mycophenolic acid acts by inhibiting inosine monophosphate deydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent on the de novo pathway for purine synthesis, including T cells.7,11,26-28... 

Kittelmann, M., Rheinegger, U., Espigat, A., Oberer, L., Aichholz, R., Francotte, E. and Ghisalba O., Preparative enzymatic synthesis of the acylglucuronide of mycophenolic acid. Adv. Synth. Catal, 2003, 345, 825. 

Mycophenolate sodium (62 Myfortic Norvatis, 2003) is an immunosuppressant drug used to prevent rejection in organ transplantation. It is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucus. In vitro, it inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, the active immunosuppressive moiety it is synthesized and administered as MMF to enhance bioavailability. 

Lai, G. Anderson, W. K. A concise synthesis of a benzimidazole analogue of mycophenolic acid using a BF3-Et20 catalyzed amino-Clai-sen rearrangement. Tetrahedron Lett. 1993, 34, 6849-6852. 

Mycophenolic acid may be obtained by the fermentation broth of Pennicillium brevicompactum. The synthesis of Mycophenolate mofetil (Patent U.S. 4,753,935). The mixture of Mycophenolic acid (32.0 g), thionyl chloride (25.0 ml) and DMF (0.3 ml) in dichloromethane (250 ml) was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford mycophenolic acid chloride as an oil. The mycophenolic acid chloride oil was dissolved in dichloromethane (50.0 ml) and added to the chilled solution of morpholinoethanol (30.5 ml) in dichloromethane (250 ml). After stirring for 90 min at 4°C, the reaction mixture was washed with water and then with aqueous sodium bicarbonate. The organic solution was dried with sodium sulfate and evaporated to yield Mycophenolate mofetil morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (melting point 93-94°C). 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Mycophenolate mofetil, the morphohnoethyl ester of mycophenolic acid (rINN), is an antimetabohte that interferes with the synthesis of nucleic acids and selectively inhibits the proliferation of T and B lymphocytes. It has been used to treat psoriasis and to prevent acute renal allograft rejection in combination with ciclosporin and glucocorticoids. 

Covarrubias-Zuniga, A., Gonzalez-Lucas, A., Dominguez, M. M. Total synthesis of mycophenolic acid. Tetrahedron 2003, 59,1989-1994. 

Mycophenolic acid and ribavarin monophosphate inhibit IMP dehydrogenase and hence GMP synthesis. 

Mycophenolate mofetil, a semisynthetic morpholinoester of my-cophenolic acid, initially was used to prevent acute rejection after renal and cardiac transplantation, but it is now used as part of combination therapy in moderate to severe psoriasis and other autoimmune dermatoses. It reversibly blocks de novo synthesis of guanine nucleotides required for DNA and RNA synthesis. The drug has been shown to have a speciflc lymphocyte antiproliferative effect. Oral mycophenolate mofetil, as well as topical mycophenolic acid, may undergo further clinical studies to establish efficacy in the treatment of patients with severe psoriasis. " ... 

Mycophenolate mofetil (Cellcept) is an immunosuppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants. Myco-phenolic acid, the active derivative of mycophenolate mofetil, inhibits the enzyme inosine monophosphatase dehydrogenase (IMPDH), thereby depleting guanosine nucleotides essential for DNA and RNA synthesis. Moreover, mycophenolic acid is a fivefold more potent inhibitor of the type 11 isoform of IMPDH found in activated B- and T-lymphocytes and thus functions as a specific inhibitor of T- and B-lymphocyte activation and proliferation. The drug also may enhance apoptosis. 

Jones conditions), aqueous acid, and mild Lewis acids.The Boc group is usually removed by treatment with aqueous HCll or with anhydrous trifluoroacetic acid. In Lai s synthesis of indole analogs of mycophenolic acid, indole derivative 143 was converted to the N-Boc compound (144) using Boc anhydride. Elaboration of the side chain in three steps was followed by deprotection with HCl in dioxane, giving 145 in 72% yield. Trifluoroacetic acid in dichloromethane converted 145 to 146 in 60% yield. 

Another acylation procedure uses iminium salts rather than acyl halides. The Vilsmeier-Haack reaction is a well-known process illustrated by reaction of pyrrole with the POCI3 complex of N,N-dimethylacetamide (207, which can decompose to a chloroiminium salt). The acylation reaction gave 208, which was converted to 2-acetylpyrrole by hydrolysis with aqueous sodium acetate.A synthetic example is taken from Lai s synthesis of indole analogs of mycophenolic acid,l in which 209 reacted with POCI3 and DMF to give a 77% yield of the aldehyde 210. 

Engel, G., von Milczewski, K. E., Prokopek, D., and Teuber, M. (1982). Strain specific synthesis of mycophenolic acid by Penicillium roqueforti in blue veined cheese. Appl. Environ. Microbiol. 43, 1034-1040. 

Mechanism of action This drug is rapidly converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of purine synthesis. This action suppresses both B and T lymphocyte activation. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for purine synthesis. 

This aromatic annulation strategy has been successfully applied in an efficient total synthesis of the antitumor antibiotic mycophenolic acid. ... 

Two further natural product-derived immunosuppressants have been introduced recently, mycophenclate scdium and everclimus (Fig. 1.7) (44). The active principle of both mycophenolate sodium and an earlier introduced form, mycophenolate mofetil (a morpholinoethyl derivative), is mycophenolic acid, obtained from several Penicillium sp. This compound is a reversible inhibitor of inosine monophosphate dehydrogenase, which is involved in guanosine nucleotide synthesis (80). 

---