Immunosuppressant Rapamycin

A striking example of a macrocyclic closure is found in the double stitching done in the final step of the synthesis of the immunosuppressant rapamycin. Bis-1,2-(tri-n-butylstannyl)ethene reacted with the diiodide to close a 31-membered ring in 28% yield at 70% conversion. The intermediate iodostannane (from a single coupling) was also isolated in about 30% yield and could be cyclized in a second step.210... 

Heitman, J., Mowa, N. R., and Hall, M. N. (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905—909. 

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. 

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... 

The Sn(II)-mediated reaction of a-alkoxythiolketene acetals with a, -unsaturated aldehydes results in enhanced reactivity and high anti selectivity in the glycolate product when an a-benzyloxy substituent is present in the aldehyde, a finding which was applied to the synthesis of a segment (C26-C33) of the immunosuppressant rapamycin (Eq. 24) [38b]. 

An intriguing new development relates to conditional protein splicing [27]. In this scenario the property of the immunosuppressant rapamycin is utilized to bind simultaneously to two different proteins (FKBP and FRB) with high affinity. If FKBP and FRB are linked to the N- and C-termini of the intein-extein halves (see Fig. 4 for the protein constructs) the addition of rapamycin would trigger the formation of a ternary complex, thereby bringing the intein halves into close proximity. In a consecutive reaction the two exteins can combine to generate an active or, e.g., fluorescent labeled protein. Since both halves can be expressed in mammalian and other cells, cellular functions can be studied. 

This section covers compounds that were reported relatively recently. The mechanism of action of these compounds is reasonably understood. The compounds in this section have been sorted by their biological activity and their potential utility in the clinic. The class of compounds include immunosuppressants (rapamycin and FK506), antitumor agents (geldanamycin to echinomycin), antiinflammatory agents (efomycin), antiobesity agents (lipstatin), and antibiotics (streptogramins to platensimycin). 

Schweeke T, Aparicio ]F, Molnar I, Konig A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortes J, Lester JB, Elohm GA, Staunton J, Leadlay PF. The biosynthesis gene duster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 1995 93 7839-7843, Decker H, Summers RG, Hutchinson CR. Overproduction of all of the components of a type II polyketide synthase or only the acyl carrier protein stimulates the production of tetra-cenomycin C biosynthetic intermediates In Streptomyees glaMcescens. J Amibioc 1994 47 54-63. 

Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol 2002 22 5575-5584. 

Polyketides are an extraordinarily valuable class of natural products, numbering over 10,000 compounds. Commercially important polyketides include antibiotics (erythromycin A, tetracycline) and immunosuppressants (rapamycin), as well as anticancer (doxorubicin), antifungal (amphotericin B), and cholesterol-lowering (lovastatin) agents (Figure 25.15). It has been estimated that the sales of these and other polyketide pharmaceuticals total more than 15 billion per year. 

In a more complex situation, LiEt3B H was employed in the synthesis of (2-hydroxy-[l,l,2,2- H]ethyl)everolimus 249, an immunosuppressant rapamycin derivative. Reduction of methyl 0-tcrt-butyldiphenylsilyl glycolate 247 followed by purification on silica... 

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