Function-oriented synthesis, step economy, and drug design.
This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, bryostatin is a unique natural product anticancer lead that restores apoptosis in cancer cells, reverses multidrug resistance, and bolsters the immune system. Remarkably, it also improves cognition and memory in animals. We have designed and synthesized simplified analogs of bryostatin that can be made in a practical fashion (pilot scale) and are superior to bryostatin in numerous assays including growth inhibition in a variety of human cancer cell lines and in animal models. Laulimalide is another exciting anticancer lead that stabilizes microtubules, like paclitaxel, but unlike paclitaxel, it is effective against multidrug-resistant cell lines. Laulimalide suffers from availability and stability problems, issues that have been addressed using FOS through the design and synthesis of stable and efficacious laulimalide analogs. Another FOS program has been directed at the design and synthesis of drug delivery systems for enabling or enhancing the uptake of drugs or drug candidates into cells and tissue. We have generated improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion. The use of FOS has allowed for the translation of exciting, biologically active natural product leads into simplified analogs with superior function. This approach enables the development of synthetically innovative strategies while targeting therapeutically novel structures.
Wender
Paul A
PA
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
Verma
Vishal A
VA
Paxton
Thomas J
TJ
Pillow
Thomas H
TH
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000191:economics*; D001685:Biological Factors / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000191:economics / Q000494:pharmacology; D015195:Drug Design; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D001685:Biological Factors; D004337:Drug Carriers