Epothiolones

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

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... 

A similar modular type arrangement of activities is present in the nonribosomal peptide synthetases (NRPS). Several examples have been described that use a hybrid PKS-NRPS system to synthesize epothiolones,370 rifamycin,371 and C-1027372 with reviews on these hybrid systems being described.373 374... 

One of the most appealing features of Pd-catalyzed cross-coupling reactions is their ability to tolerate a wide variety of functional groups. This feature allows for these reactions to be implemented towards the end of a total synthesis. This is exemplified in the preparation of Epothiolone B analogs [59]. Stille reaction of tributylstannylpyrimidine derivative 140 with the highly functionalized vinyl iodide 139 provides the desired Epothiolone B analog 141. 

Beck WT, Cass CE, Houghton PJ. Microtubule-targeting anticancer drugs derived from plants and microbes vinca alkaloids, taxanes, and epothiolones. In Bast RC Jr, Kufe DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E III, eds. Holland-Frei Cancer Medicine. 5th Ed. Hamilton, Ontario BC Decker, 2000 680-698. 

One of the earliest researchers in the area of natural product-like libraries is K.C. Nicolaou. Inspired by the total synthetic efforts of his group on many important natural product targets and coupled with his interest in synthetic methodology and chemical biology, Nicolaou reported a number of elegant examples (see Chapter 11) that include natural product-like libraries based upon Taxol, " sarcodictyins, epothiolones, vancomycin, muscone, and psammaplin a. ... 

Epothilones (Anticancer drugs) Microbial Hydroxylation of Epothiolone B to Epothilone F... 

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