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2 2009

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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].

Desmuramylopeptydy - struktura i aktywność biologiczna

Dzierzbicka K., Sągol K., Wardowska A., Trzonkowski P.

Wiadomości Chemiczne

2009

[Z] 63, 11-12

1089-1114

Bacterial cell wall peptidoglycan (PGN) is a potent immunostimulator and immune adjuvant. Numerous studies reported on immunoactivities of bacterial PGN, most of which have been reproduced by a chemically synthesized low-molecular PGN fragment, muramyldipeptide (MDP) 1 (Fig. 1) [2, 4, 5, 7, 8, 10, 13]. Another type of PGN fragment, desmuramylpeptides (DMPs), has also been chemically synthesized to mimic PGN containing meso-DAP, and the DMPs exerted similar bioactivities to MDP. In 1984 [18] reported that y-D-Glu-meso-DAP was the minimum structural unit capable of eliciting bioactivities induced by DMPs. Recently demonstrated that intracellular protein carrying a nucleotidebinding oligomerization domain (NOD), NOD2 an intracellular receptor for MDP and DMPs containing DAP was recognized by another NOD protein, NOD1 [8, 33]. Replacement of the N-acetylmuramyl moiety with various acyl groups thus represents an important approach to the design and synthesis of new immunologically active MDP analogues – desmuramylpeptides, e.g. FK-156 9, pimelautide 11 (Fig. 2), 7-(oxoacyl)-L-alanyl-D-isoglutamines, carbocyclic MDP analogues (Fig. 13) [3, 13] in which a more lipophilic cyclohexane ring is present instead of the polyhydroxy pyranose ring of D-glucosamine, and the adamantyl-substituted MDP analogue LK-415 (Fig. 8) [54]. The FK-156 isolated from Streptomyces olivaceogriseus [21, 22] and its synthetic analogue of FK-565 10 (Fig. 2) have been reported to be a potent stimulant of antibody production and free of pyrogenicity. These compounds with close structural resemblance to bacterial cell wall peptidoglycan peptides, exhibit very interesting biological activities. Both FK-156 10 and FK-565 11 (Fig. 3) enhance host defense ability against microbial infections, exhibit strong antiviral activity and remarkable antitumor potency [2, 13, 14, 18]. Also other acyl-DMPs were obtained and their activity described (Table 1). The most promising DMPs analogues were series of phthalimido-DMPs 46-53 (Fig. 7). In these compounds N-acetylmuramic acid residue was replaced by various N-phthaloylated amino acids [42–49] or phthalimido substituted aminoethoxyacetic acid to give immunologically active acyclic MDP analogues like LK-423 46 (LK-413 47, LK-511 48, LK-512 49, LK-508 50) (Fig. 7) [42, 47–49]. LK-423 has been selected for further studies to develop an anti-inflammatory pharmaceutical agent. In 2001 Gobec et al. [54] reported the synthesis of new adamantyl-DMPs LK-415 55 and LK-517 56 (Fig. 8) with 1-adamantyl-carboxamido moiety replacing N-acetylglucosamine fragment in MDP. Their efficiency in modulating the production of cytokines IL-12, TNFá, IFNă, IL-4, and IL-10 was measured in vitro in ionomycin and PMA activated cultures of PBMC, co-incubated with the analogues tested. The results were compared with the activity of MDP. All substances were strong regulators of IL-12 synthesis and IFNă synthesis as well. Introduction of diethyl phosphonate moiety into LK-517 was of great importance for augmented T-cell cytokine production. Dzierzbicka et al. [55] described synthesis of three analogues of DMPs 57a,b, 58 modified with an amino-acridine/acridone residue. The screening data indicate that the analogues 57a,b and 58 (Fig. 9) exhibit low cytotoxic activity. Uehara et al. [59] reported MDP and DAP-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists (Fig. 10) synergistically induced production of IL-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. In 2008 Kawasaki et al. [33] designed synthesis of DAP containing PGN fragments and tracheal cytotoxin (TCT) (Fig. 5) and investigated their biological activity. Recently, N-acetylglucosamine- 1,6-anhydro-N-acetylmuramylpentapeptide (Fig. 12) and evaluation of its turnover by AmpD from Escherichia coli has been reported [61]. The synergism of MDP and DMPs with other chemotherapeutics is also promising in the therapy of many infectious and anticancer diseases. This paper reviews the most important approaches to desmuramylpeptides (DMPs), their derivatives and displays structure-reactivity relationships of these compounds.