Kwas mykofenolowy i jego analogi. Synteza i aktywność biologiczna

• Autorzy: Małachowska M. , Cholewiński G. , Dzierzbicka K. , Wardowska A. , Trzonkowsk P.

Warianty tytułu

EN

Mycophenolic acid (mpa) and its analogues. synthesis and biological activity

• Języki publikacji: PL

Abstrakty

EN

Mycophenolic acid (MPA) 1 is one of the most substituted phtalides. Its chemical structure incorporates a highly functionalized, hexasubstituted benzene ring [3, 4]. This compound is one of the oldest known antibiotics [1, 2]. MPA is the most potent uncompetitive inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH). This enzyme catalyzes a rate - limiting step in the de novo biosynthesis of purine nucleotides [13]. Mycophenolic acid as an IMPDH inhibitor functions as antifungal, antiviral, antibacterial and immunosupressive agent [5-11]. Its derivatives: mycophenolate mofetil (MMF; CellCept(r), Roche AG) and mycophenolate sodium (MPS; Myfortic(r), Novartis Pharma AG) are used in combination with corticosteroids and calcineurin inhibitors (cyclospo-rine A or tacrolimus) for the treatment and prophylaxis of organ rejection in solid organ transplants. The metabolic lability of mycophenolic acid and severe side effects in clinical treatment are the main reasons for the development of new synthetic pathways of its derivatives [14]. This paper reviews the most important approaches in mycophenolic acid synthesis and its derivatives and displays structure-reactivity relationships of these compounds. Synthesis of mycophenolic acid as one of the highest substituted phtalide is described [23-35]. The most common synthetic approach in preparation of highly substituted benzenes is by using benzene ring constructions with five or six required substituents [28-30]. First of these methods [25] is based on construction of the pentasubstituted resorcinol derivative via thermal addition of the alkynyl ether to the cyclobutenone. The synthetic strategy of the second method [28, 30] is depicted in Scheme 4 and the key step of this approach involves reaction between 16 and 17. Alternative approach to total mycophenolic acid synthesis is preparation of its intermediates [31]. Mycophenolic acid derivatives were divided into five groups, according to their chemical structure. For each of them synthetic pathway was shown and structure-biological activity relationships were described [40]. It has been found that replacement of the mycophenolic acid lactone ring with other cyclic groups resulted in loss of potency. A phenolic hydroxyl group and the aromatic methyl substituent were found to be essential for high activity. Replacement of the methoxy group with ethyl, vinyl or methyl resulted in compounds with higher activity than mycophenolic acid itself [41]. It has also been discovered that substitution with small alkyl groups in the ? position to the carboxylic group results in enhanced potency [46]. Furthermore monocyclic and indol derivatives were obtained and the carboxyamide derivative was selected for screening against prostate cancer [54]. Also new monocyclic analogues were obtained but they did not show any anticancer activity [55]. There have been synthesized several analogues of mycophenolic adenine dinucleotide [50-52] or mycophenolic adenine methylene-bis(sulfonamide)s [53] which showed inhibitory activity against IMPDH. Recently, a series of novel IMPDH inhibitors based on a methoxy-(5-oxazolyl)-phenyl (MOP) moiety have been designed [56].

Słowa kluczowe

PL

kwas mykofenolowy; MPA; synteza; analogi MPA; aktywność biologiczna

EN

mycophenolic acid; MPA; synthesis; MPA analogues; biological activity

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2009
• Tom: [Z] 63, 3-4
• Strony: 309--332
• Opis fizyczny: bibliogr. 56 poz., wykr.

Twórcy

autor

Małachowska M.

autor

Cholewiński G.

autor

Dzierzbicka K.

autor

Wardowska A.

autor

Trzonkowsk P.

• Katedra Chemii Organicznej, Wydział Chemiczny, Politechnika Gdańska, ul. G. Narutowicza 11/12, 80-952 Gdańsk

Bibliografia

• [1] R. Bentley, Chem. Rev., 2000, 100, 3801.
• [2] Merck Index., 2006, 14, 1094.
• [3] P.W. Clutterbuck, H. Raistrick, Biochem. J., 1933, 27, 654.
• [4] J.H. Birkinshaw, H. Raistrick, D.J. Ross, Biochem. J., 1952, 50, 630.
• [5] E.P. Abraham, Biochem. J., 1945, 39, 398.
• [6] T. Noto, M. Sawada, K. Ando, K.J. Koyama, J. Antibiot., 1969, 22, 165.
• [7] J.A. Gallagher, C.M. Quinn, P.A. Whittaker, Biochem. Soc. Trans., 1987, 15, 290.
• [8] R.H. William, D.H. Lively, D.C. De Long , J.C. Cline, M.J. Sweeney, G..A. Poore, S.H. Larsen, J. Antibiot., 1968, 21, 463.
• [9] C. Alfieri, A.C. Alison, E. Kieff, Antimicrob. Agents. Chemother., 1994, 38, 126.
• [10] Merck Manual., 2006, 18, 1779 (Wydanie Trzecie Polskie).
• [11] F.A. Elbarbry, A.S. Shoker, Clin. Biochem., 2007, 40, 752.
• [12] J.C. Wu, Perspect. Drug Discovery Des., 1994, 2, 185.
• [13] C. Papageorgiu, Mini-Rev. Med. Chem., 2001, 1.
• [14] J. Lintrup, P. Hyltoft-Petersen, S. Knudtzon, N.I. Nissen, Cancer Chemother. Rep-Part I, 1972, 56, 229.
• [15] W.W. Epinette, C.M. Parker, E.L. Jones, M.C. Greist, J. Am. Dermatol., 1987, 17, 962.
• [16] J. Podlewski, A. Chwalibogowska-Podlewska, Leki Wspó³czesnej Terapii, 2001, s. 421.
• [17] K.M. David, J.A. Morris, B.J. Steffen, K.S. Chi-Burris, V.P. Gotz, R.D. Gorgon, Clin. Transplant., 2005, 19, 279.
• [18] S.R. Lederer, N. Friedrich, B. Banas, G. Welser, E.D. Albert, T. Sitter, Clin. Transplant., 2005, 19, 168.
• [19] C.C. Baan, A.H. Balk, I.C. van Riemsdijk, P.J. Vamtrimpont, A.P. Maat, H.G. Niesters, P.E. Zondervan, T. van Gelder, W. Weimar, Transplantation, 2003, 75, 1704.
• [20] B. Kaplan, Curr. Med. Res. Opin., 2006, 22, 2355.
• [21] R.D. Ensley, M.R. Bristow, S.L. Olsen, D.O. Taylor, E.H. Hammond, J.B. O'Connell, D. Dunn, L. Osburn, K.W. Jones, R.S. Kauffman, Transplantation, 1993, 56, 75.
• [22] M. Sandor, S. Csaba, Patent EP 1908756, 2008.
• [23] S. Anindya, S. Shrikumar, K.A. Prakash, S. Pampapayhy, T.S. Pradeep, Patent WO 0164931, 2003.
• [24] K. Vilmos, C. Zoltan, Patent WO 2005105768, 2007.
• [25] A.J. Birch, J.J. Wright, Aust. J. Chem., 1969, 22, 2635.
• [26] J.W. Patterson, Tetrahedron, 1993, 49, 4789.
• [27] L. Canonica, B. Rindone, E. Santaniello, C. Scolastico, Tetrahedron, 1972, 28, 4395
• [28] R.L. Danheiser, S.K. Gee, J.J. Perez, J. Am. Chem. Soc., 1986, 108, 806.
• [29] A. Covarrubias-Zúńiga, A. Gonzàlez-Lucas, Tetrahedron Lett., 1998, 39, 2881.
• [30] A. Covarrubias-Zúńiga, J. Diaz-Dominguez, J.S. Olguin-Uribe, Synth. Commun., 2001, 31, 1373.
• [31] A. Covarrubias-Zúńiga, A.Gonzàlez-Lucas, M.M. Dominguez, Tetrahedron, 2003, 59, 1989.
• [32] P.A. Plé, A. Hamon, G. Jones, Tetrahedron, 1997, 53, 3395.
• [33] M. Abdurrazzaque, K. Rudolf, Patent US 2008300404, 2008.
• [34] P. De, R. Mattheus, V.B. De Erik, T. Neeraj, G.B. Nana, Patent WO 2009003878, 2009.
• [35] R.B. Wagner, H.D. Zook, Synthetic Organic Chemistry, 1956, 479-532.
• [36] M.D. Sintchak, E. Nimmesgern, Immunopharmacol., 2000, 47, 163.
• [37] M.D. Sintchak, M.A. Fleming, O. Futer, S.A. Raybuck, S.P. Chambers, P.R. Caron, M.A. Murcko, K.P. Wilson, Cell, 1996, 85, 921.
• [38] L. Chen, R. Petrelli, K. Felczak, G. Gao, L Bonnac, J.S. Yu, E.M. Bennett, K.W. Pankiewicz, Curr. Med. Chem., 2008, 15, 650.
• [39] E.B. Sjogven, World Patent WO 22535, 1995.
• [40] P.H. Nelson, S.F. Carr, B.H. Devens, E.M. Eugui, F. Franco, C. Gonzalez, R.C. Havley, D.G. Loghhead, D.J. Milan, E. Papp, J.W. Patterson, S. Rouhafza, E.B. Sjogren, D.B. Smith, R.A. Stephenson, F.X. Talamas, A.-N. Waltos, R.J. Weikert, J.C. Wu, J. Med. Chem., 1996, 39, 4181.
• [41] D.F. Jones, S.D. Mills, J. Med. Chem., 1971, 14, 305.
• [42] M.J. Sweeney, K. Gerzon, P.N. Harris, R.E. Holmes, G.A. Poore, R.H. Williams, Cancer Res., 1972, 32, 1795.
• [43] J.W. Patterson, D. Morgans JR, D.B. Smith, F.X. Talamas, D.R. Artis, A. Cervantes, T.R. Elworthy, M. Fernandez, F. Franco, R.C. Hawley, T. Lara, D.G. Loughhead, P.H. Nelson, E.B. Sjogren, A. Trejo, A.M. Waltos, R.J. Weikert, Patent US 5444072, 2000.
• [44] Y.S. Or, L. Liu, B. Lane, G. Hsieh, D. Sweeney, K.W. Mollison, J.R. Luly, Division of Medicinal Chemistry Society, Washington, DC, 1994, p. 112.
• [45] L. Chen, D. Wilson, H.N. Jayaram, K.W. Pankiewicz, J. Med. Chem., 2007, 50, 6685.
• [46] J.C. Rohloff, J.O. Gardner, R.W. Towne, Tetrahedron Lett., 1995, 36, 7803.
• [47] M. Fernández-Zertuche, R. Robledo-Perez, M.E. Meza-Avińa, M. Ordonez-Palacios, Tetrahedron Lett., 2002, 43, 3777.
• [48] W.J. Watkins, J.M. Chen, A. Cho, L. Chong, N. Collins, M. Fardis, W. Huang, M. Hung, T. Kirschberg, W.A. Lee, X. Liu, W. Thomas, X. Xu, A. Zeynalzadegan, J. Zhang, Bioorg. Med. Chem. Lett., 2006, 16, 3479.
• [49] D.R. Artis, T.R. Elworthy, R.C. Hawley, D.G. Loughhead, D.J. Morgans JR, P.H. Nelson, J.W. Patterson JR, J.C. Rohloff, E.B. Sjogren, D.B. Smith, A.M. Waltos, R.J. Weikert, A.C. Garcia, M.F Zertuche, F.F. Andrade, M.T.L. Hernandez, F.X.T. Murra, T.A.T. Martion, Patent WO 9522538, 1995.
• [50] K.W. Pankiewicz, K.B. Lesiak-Watanabe, K.A. Watanabe, S.E. Patterson, H.N. Jayaram, J.A. Yalowitz, M.D. Miller, M. Seidman, A. Majumdar, G. Prehna, B.M. Goldstein, J. Med. Chem., 2002, 45, 703.
• [51] D. Rejman, M. Olesiak, L. Chen, S.E. Petterson, D. Wilson, H.M. Jayaram, L. Hedstrom, K.W. Pankiewicz, J. Med. Chem., 2006, 49, 5018.
• [52] L. Chen, G. Gao, K. Felczak, L. Bonnac, S.E. Petterson, D. Wilson, E.M. Bennett, H.M. Jayaram, L. Hedstrom, K.W. Pankiewicz, J. Med. Chem., 2007, 50, 5743.
• [53] L. Chen, R. Petrelli, M. Olesiak, D.J. Wilson, N.P. Labello, K.W. Pankiewicz, Bioorg. Med. Chem., 2008, 16, 7462.
• [54] G. Lai, W.K. Anderson, Tetrahedron, 2000, 56, 2583.
• [55] M.E. Meza-Avińa, M. Ordońez, M. Fernández-Zertuche, L. Rodriguez-Fragoso, J. Reyes-Esparza, A.A.M. de los Rios-Corsino, Bioorg. Med. Chem., 2005, 13, 6521.
• [56] L. Chen, D.J. Wilson, N.P. Labello, H.M. Jayaram, K.W. Pankiewicz, Bioorg. Med. Chem., 2008, 16, 9340.