Meeting the challenge: A reliable and modular reaction sequence has been developed for the synthesis of the challenging tubulysin framework. This route allows preparation of hundreds of milligrams of the stereochemically pure tetrapeptides (see picture), which are produced in small amounts by two different species of myxobacteria. Thus, full biological evaluation of the tubulysins and their analogues is now a real possibility.

Cancer chemotherapy relies on the expectation that anticancer drugs will preferentially kill rapidly dividing tumor cells rather than normal cells. As a large portion of the tumor cells must be killed to obtain and maintain a complete remission, large drugs doses are typically used, with significant toxicity toward proliferating nonmalignant cells. Indeed, the majority of pharmacological approaches for the treatment of solid tumors suffers from poor selectivity, thus limiting dose escalation (that is, the doses of drug required to kill tumor cells cause unacceptable toxicities to normal tissues).The development of more selective anticancer drugs with an improved ability to discriminate between tumor cells and normal cells is possibly the most important goal of modern anticancer research. For this reason, there is much current interest in the development of new cytotoxic chemical entities with improved selectivity toward tumor cells and lower systemic toxicity. A highly promising strategy is based on the discovery that many tumors overexpress specific protein markers at the site of neoplasia, suggesting the possibility of implementing a ligand-based selective targeted delivery of drugs to the cancer cells and/or the tumor stroma.[1] Indeed, a tumor-associated antigen can often be targeted by a monoclonal antibody (mAb) with suitable affinity and specificity. The pharmacokinetic properties of mAbs can be modulated by the choice of the recombinant antibody format, which ranges from the small scFv antibody fragments (which typically exhibit 90 % clearance from the circulatory system within 1 hour) to the full immunoglobulins IgG (which display a half-life of weeks for the beta phase of blood clearance). Furthermore, mAbs and their fragments can be engineered to carry functional groups suitable for chemical modification such as C-terminal cysteine residues for selective coupling with thiol-reactive compounds. These features make mAbs excellent vehicles for the targeted delivery of cytotoxic drugs to the tumor in the form of an antibody-drug conjugate, whereas mAbs themselves are often only weakly cytotoxic and therefore not therapeutically useful.[2] Mylotarg (Wyeth) is the first example of a recently approved mAb-cytotoxic drug conjugate for cancer therapy. [3] Considering the difference in molecular weight between antibodies and cytotoxic molecules, and the fact that the injection of large quantities of antibody (> 100 mg) into patients is not desirable for cost-of-goods considerations, it is intuitive to see that ideal drugs for targeted delivery applications should be capable of killing cells in the sub-nanomolar concentration range and should carry suitable functional groups for coupling to antibody molecules. Such highly potent drugs may allow the use not only of internalizing antibodies, but also of antibodies directed against the more abundant and stable stromal antigens, provided that a suitable hydrolytic mechanism is available for the liberation of the drug at the tumor site. Maytansanoids, auristatins, tax...

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