Rapamycin, discovery

The discovery and characterization of novel small molecule inhibitors that target the ribosome recruitment step of translation initiation is extremely important in order to validate translation initiation as a chemotherapeutic target. Rapamycin, an inhibitor of TOR (target of rapamycin) complex I... 

A major advantage of the natural products approach to drug discovery is that it is capable of providing complex molecules that would not be accessible by other routes. Compounds such as paclitaxel (Taxol, 8) or rapamycin (10) would never be prepared by standard "medicinal chemistry" approaches to drug discovery, even including the newer methods of combinatorial chemistry. Likewise, the new approach of combinatorial biosynthesis, although an important one, is unlikely in the near future to yield new compounds of the complexity of paclitaxel and camptothecin. 

Medicinal and herbal extracts form the basis for the health care of approximately 80% of the world s population some 21,000 plant species are used world-wide. Screening of natural products led to the discovery of the immunosuppressants, cyclosporin, rapamycin, and FK 506 (153), and there is a continued search for new compounds, even in relatively well-explored areas such as China (154). 

Shortly after the discovery of calcineurin as the mechanistic key for FK506 and CsA action, the mechanism of action of rapamycin began to unfold. It had already been noted that rapamycin blocked the IL-2 stimulated G1 to S phase transition in T-cells, inhibiting cell division. Treatment of T-cells with rapamycin was found to result in decreased enzymatic activity of several kinases, including p70 S6 kinase (a 70 kDa protein which phosphorylates the S6 protein of the small ribosomal subunit),27-29 and cyclin-dependent kinases of 33 and 34 kDa.30,31 However, in vitro experiments demonstrated that these kinases were not directly inhibited by the FKBP-rapamycin complex. In 1993, two yeast proteins were identified that appeared to be involved in the mechanistic pathway and mutations in these proteins conferred resistance to rapamycin-induced cytotoxicity.32 These proteins were named TORI and TOR2 (targets of rapamycin). 

Direct site-selective functionalization of natural products is a powerful tool for the discovery of drug candidates because nature provides a rich pool of unique molecular frameworks with diverse biological profiles [32,33], Acylation of a particular hydroxy group among multiple hydroxy groups in polyol natural products has been well studied by means of enzymatic protocol [34], For example, acylation of rapamycin, an immunosuppressive agent, took place at C(42)-OH selectively in the presence of PSL-C to provide an anticancer agent, temsirolimus (Scheme 13) [35]. Inspired by these achievements, extensive efforts have been devoted to develop the non-enzymatic counterparts toward site-selective functionalization of polyol natural products [4],... 

The discovery of the immunosuppressant effects of rapamycin, FK506, and ascomycin has sparked renewed fervor in secondary metabolic studies, provided a new class of immunosuppressants, and led to a greater understanding of the immune response. It is impossible to predict what advances and in which directions the field of natural products research will take us in the next century. What is cleat, however, is that in an era of combinator-... 

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