Immunosuppressants, polyketides

For their 2010 synthesis of the immunosuppressive polyketides dalesconols A and B [143], Snyder and co-workers developed an outstanding one-pot cascade to forge the bicyclo[5.3.0]decanyl core of these targets from the judiciously functionalized and protected precursors 276. The ultimate addition of DIB in TFE at low temperature served to transform in situ the phenols 277 into the five-membered carbo-spirocyclic cyclohexa-2,5-dienone intermediates 278, which were then efficiently converted into dalesconols A and B (Fig. 67) [143]. 

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

The polyketides are a large family of bio synthetically related NPs, some of which have very great pharmaceutical value (polyketide sales total about 10 billion annually, see also Chapter 7). Some antibiotics (erythromycin, monensin, rifamycin), immunosuppressants (rapamycin), antifungal substances (amphotericin), antiparasitic (aver-mectin) and anticancer drugs (doxorubicin) are polyketides. The term polyketide refers to the fact that the basic carbon skeleton is not a simple hydrocarbon chain as in the case of fatty acids but is a series of linked keto groups in sequence (Figure 3.6). The first phase of this pathway, the generation of carbon skeleton diversification. 

Figure 2 Examples of polyketides. Polyketides demonstrate a broad range of biological activities, including antibiotic (oxytetracycline and erythromycin), antitumor (doxorubicin and dynemicin), antiparasitic (avermectin), and immunosuppressive (FK506). Monensin is used as a bovine feed supplement and an anticoccidial agent.

T Schweke, JF Aparicio, I Molnar, A Konig, LE Khaw, SF Haydock, M Oliynyk, P Caffrey, J Cortes, JB Lester, G Bohm, J Staunton, PF Leadlay. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci... 

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

One new wrinkle on the combinatorial strategy involves a process referred to as combinatorial biosynthesis. In this situation, bacterial gene expression is altered in the hope of changing the structure and function of specific enzymes. For example, one class of potential bacteria-derived drugs are the polyketides, which may have antibiotic, immunosuppressant, and anticancer activity. Bacteria produce polyketides with the help of a family of enzymes known as polyketide synthases (PKSs). To date, most of the normally produced polyketides screened have shown little activity. 

One of the most exciting areas in the field of multifunctional enzyme systems is the synthesis of a wide array of organic molecules by polyketide and nonribosomal protein synthetases. These enzymes are generally characterized by multiple subunits which themselves consist of individual domains with distinct enzymatic activities (Fig. 9.11a). The range of natural products synthesized by these mega-synthetases includes a considerable number of important antibiotics, antifungals, antitumor and cholesterol-lowering compounds, immunosuppressants, and siderophores. 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

Shim JH, Lee HK, Chang EJ, Chae WJ, Han JH, Han DJ, Morio T, Yang JJ, Bothwell A, Lee SK. Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction. Proc. Natl. Acad. Sci. U.S.A. 2002 99 10617-10622. Choi SS, Hur YA, Sherman DH, Kim ES. Isolation of the biosynthetic gene cluster for tautomycetin, a linear polyketide T cell-specific immunomodulator from Streptomyces sp. CK4412. Microbiology 2007 153 1095-1102. 

K. O. Stmctural organization of a multifunctional polyketide synthase involved in the biosynthesis of the macrolide immunosuppressant FK506. Eur.]. Biochem. 244, 74-80 (1997). 

Recently, it has been noticed that natural products with polyketide units can be potent immunosuppressive agents as well as antitumor agents. Two structurally different polyketide lactones, discodermolide and pironetin belong to this group of compounds (Fig. 1). Due to the potential therapeutic applications and the extreme scarcity of discodermolide and pironetin, interest in the chemical synthesis of these two natural products and in their analogues continues unabated. 

Other medically important polyketides include the antibiotics doxorubicin (14-hydroxydaunomycin Fig. 5-23), rifamycin (Box 28-and the antifimgal pimaricin, griseofulvin, and amphotericin (Fig. 21-10), the HMG-CoA reductase inhibitor lovastatin, the 2-butanyl-4-methylthreonine of cyclosporin A (Box 9-F), and other immunosuppressants such as rapamycin. Many characteristic plant products, including stilbenes and chalcones (Box 21-E), are polyketides. A variety of different polyketides serve as phytoalexins. Some such as aflatoxin are dangerous toxins. Ants and ladybird beetles make toxic polyamine alkaloids using a polyketide pathway. ... 

Polyketides represent a large and diverse group of natural products with an impressive wealth of anticancer, immunosuppressive, antipaiasitic and antimicrobial activities. Tliese natural products ai e assembled by polyketide synthases in a conimon pathway tliat resembles fatty acid biosynthesis. Simple units such as malonyl-CoA and nietliyhiialonyl-CoA are used in decai boxylative condensations to gi ow a polyketide chain from a staiter unit such as propionyl-CoA. Var iations in the number of extensions, choice of stai ter units and extender units, and the amount and stereocliemish y of reduction of tlie polyketide chain after each condensation, all contribute to the shiictural diversity of tliese natural products. More shiictui al diversity is accomplished by glycosylases, metliyltransferase and oxidases, which act on these polyketide stractures. 

An enormous range of medically important polyketide and peptide natural products assembled by modular polyketide synthases (PKSs), non-ribosomal peptide synthases (NRPSs) and mixed PKS/NRPS systems have macrocyclic structures, including the antibiotics erythromycin (PKS) and daptomycin (NRPS), the immunosuppressants cyclosporin (NRPS) and rapamycin (PKS/NRPS), and the antitumor agent epothilone (PKS/NRPS). PKSs and NRPSs are large, multifunctional proteins that are organized into sets of fnnc-tional domains termed modules. The order of modules corresponds directly to the seqnence of monomers in the product. Synthetic intermediates are covalently tethered by thioester linkages to a carrier protein domain in each module. The thiol tether on each carrier domain is phosphopantetheine, which is attached to a conserved serine residne in the carrier protein in a post-translational priming reaction catalyzed by a phosphopantetheinyltransferase. 

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