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Poszukiwanie nowych leków immunosupresyjnych

Dzierzbicka K., Cholewiński G., Iwaszkiewicz-Grześ D., Trzonkowski P.

Wiadomości Chemiczne

2011

[Z] 65, 1-2

59-92

Transplantology is getting more and more important in medicine. Development of surgical techniques and immunosuppressive treatment enabled to establish successful transplantations with various organs and tissues. However, allografts are recognized as foreign tissues and stimulate rejection, i.e. a strong immunological response which, if not stopped, results in complete destruction of the transplanted tissue. In order to prevent the rejection patients have to be treated with immunosuppressive drugs after transplantation. Unfortunately, such a damping of immune system poses a risk of cancer or severe infections. The treatment itself is also toxic, notably when applied in a long-term maintenance therapy. Currently, adverse effects of immunosuppressive drugs are recognized as the ones to be involved significantly in chronic rejection and limitation of long survival of grafted tissues. Whereas prevention of acute rejection is mostly successful, there is still no efficient treatment for chronic graft rejection. Reduction of a dose of immunosuppressive drugs or an invention of new active substances is considered the most promising solution. Nowadays, immunosuppressive drugs can be divided into the three main groups: agents which inhibit production of cytokines taking part in cells’ activation (glicocorticosteroids, calcineurine inhibitors, mTOR inhibitors), antiproliferative compounds (azathiopirin, mycophenolate mofetil, mycophenolic acid sodium salt), and antibodies. In this article we present new investigations towards immunosuppressive drugs, their structures and synthetic methods.

Kwas mykofenolowy i jego analogi. Synteza i aktywność biologiczna

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

Wiadomości Chemiczne

2009

[Z] 63, 3-4

309-332

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].