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.

[1]  M. Huffman.  Self-Medicative Behavior in the African Great Apes: An Evolutionary Perspective into the Origins of Human Traditional Medicine , 2001 .

[2]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[3]  B. Roth,et al.  The discovery and development of atorvastatin, a potent novel hypolipidemic agent. , 2002, Progress in medicinal chemistry.

[4]  M. Miller,et al.  Reduction of Escherichia coli O157:H7 and Salmonella in ground beef using lactic acid bacteria and the impact on sensory properties. , 2005, Journal of food protection.

[5]  M. Schnute,et al.  The First Formal Asymmetric Synthesis of Phorbol , 1997 .

[6]  P. Wender,et al.  New reactions and step economy: the total synthesis of (±)-salsolene oxide based on the type II transition metal-catalyzed intramolecular [4 + 4] cycloaddition , 2006 .

[7]  Lori L. Rodgers,et al.  The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. , 1991, Journal of natural products.

[8]  Mark Hildebrand,et al.  Identification of the putative bryostatin polyketide synthase gene cluster from "Candidatus Endobugula sertula", the uncultivated microbial symbiont of the marine bryozoan Bugula neritina. , 2007, Journal of natural products.

[9]  Lei Zhang,et al.  Total synthesis of (-)-laulimalide. , 2000, Journal of the American Chemical Society.

[10]  S. Korsmeyer,et al.  Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix , 2004, Science.

[11]  A. Szallasi,et al.  Euphorbium: modern research on its active principle, resiniferatoxin, revives an ancient medicine. , 1997, Life sciences.

[12]  J. Ajani,et al.  A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma , 2006, Investigational New Drugs.

[13]  J. Mulzer,et al.  Microtubule-stabilizing marine metabolite laulimalide and its derivatives: synthetic approaches and antitumor activity. , 2003, Chemical reviews.

[14]  E. Carreira,et al.  Total Synthesis of Bryostatin 2 , 1999 .

[15]  P. Blumberg,et al.  Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C). , 2003, Accounts of chemical research.

[16]  K. Pattabiraman,et al.  An efficient, scalable synthesis of the molecular transporter octaarginine via a segment doubling strategy. , 2001, Organic letters.

[17]  A. Mayweg,et al.  A concise, selective synthesis of the polyketide spacer domain of a potent bryostatin analogue. , 2003, Organic letters.

[18]  Paul A Wender,et al.  Synthesis and PKC binding of a new class of a-ring diversifiable bryostatin analogues utilizing a double asymmetric hydrogenation and cross-coupling strategy. , 2006, Organic letters.

[19]  J. Rothbard,et al.  Molecular Transporters: Synthesis of Oligoguanidinium Transporters and Their Application to Drug Delivery and Real‐Time Imaging , 2006, Chembiochem : a European journal of chemical biology.

[20]  H. Mackay,et al.  Protein kinase C: a target for anticancer drugs? , 2003, Endocrine-related cancer.

[21]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[22]  T. Meyer,et al.  Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog. , 2004, Current drug discovery technologies.

[23]  R. Mohammad,et al.  Bax:Bcl-2 ratio modulation by bryostatin 1 and novel antitubulin agents is important for susceptibility to drug induced apoptosis in the human early pre-B acute lymphoblastic leukemia cell line, Reh. , 1999, Leukemia research.

[24]  Thomas M. Razler,et al.  Design and synthesis of a potent phorboxazole C(11-15) acetal analogue. , 2006, Organic letters.

[25]  P. Wender,et al.  Microtubule-stabilizing agents based on designed laulimalide analogues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  S. Taylor,et al.  Protein kinase inhibition: natural and synthetic variations on a theme. , 1997, Current opinion in chemical biology.

[27]  C. Contag,et al.  Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice , 2007, Proceedings of the National Academy of Sciences.

[28]  Blaise Lippa,et al.  The practical synthesis of a novel and highly potent analogue of bryostatin. , 2002 .

[29]  Vishal A. Verma,et al.  Design, synthesis, and biological evaluation of a potent, PKC selective, B-ring analog of bryostatin. , 2006, Organic letters.

[30]  K. Pattabiraman,et al.  The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Mooberry,et al.  Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. , 1999, Cancer research.

[32]  P. Wender,et al.  Laulimalide and synthetic laulimalide analogues are synergistic with paclitaxel and 2-methoxyestradiol. , 2006, Molecular pharmaceutics.

[33]  G. E. Atilla‐Gokcumen,et al.  Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors , 2007 .

[34]  Paul A Wender,et al.  Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy. , 2006, Organic letters.

[35]  P. Wender,et al.  Studies on DNA-cleaving agents: synthesis of a functional dynemicin analogue , 1991 .

[36]  N. Lindquist,et al.  Potent cytotoxins produced by a microbial symbiont protect host larvae from predation , 2004, Oecologia.

[37]  J. Luengo,et al.  Structure-activity studies of nonmacrocyclic rapamycin derivatives , 1993 .

[38]  J. Rothbard,et al.  Polyarginine enters cells more efficiently than other polycationic homopolymers. , 2000, The journal of peptide research : official journal of the American Peptide Society.

[39]  J. Rehg,et al.  Effect of CD40 ligand and other immunomodulators on Pneumocystis carinii infection in rat model. , 2000, Microbial pathogenesis.

[40]  G. Peters,et al.  Modulation of resistance to ara-C by bryostatin in fresh blast cells from patients with AML. , 1998, Leukemia research.

[41]  Taeyoung Yoon,et al.  The Total Synthesis of Dynemicin A Leading to Development of a Fully Contained Bioreductively Activated Enediyne Prodrug , 1996 .

[42]  Carl O. Pabo,et al.  Cellular uptake of the tat protein from human immunodeficiency virus , 1988, Cell.

[43]  K. Koehler,et al.  Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Lei Zhang,et al.  Synthesis and biological evaluation of (-)-laulimalide analogues. , 2003, Organic letters.

[45]  Arun K. Ghosh,et al.  The microtubule stabilizing agent laulimalide does not bind in the taxoid site, kills cells resistant to paclitaxel and epothilones, and may not require its epoxide moiety for activity. , 2002, Biochemistry.

[46]  P. O’Neill,et al.  Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. , 2004, Accounts of chemical research.

[47]  M. Eguchi.  Recent advances in selective opioid receptor agonists and antagonists , 2004, Medicinal research reviews.

[48]  Paul A Wender,et al.  Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs. , 2006, Organic letters.

[49]  P. Wender,et al.  The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Evan W. Miller,et al.  Molecular imaging of hydrogen peroxide produced for cell signaling , 2007 .

[51]  Priscille Brodin,et al.  A Truncated HIV-1 Tat Protein Basic Domain Rapidly Translocates through the Plasma Membrane and Accumulates in the Cell Nucleus* , 1997, The Journal of Biological Chemistry.

[52]  Deborah M Gordon,et al.  Structural complexity of chemical recognition cues affects the perception of group membership in the ants Linephithema humile and Aphaenogaster cockerelli , 2007, Journal of Experimental Biology.

[53]  P. Crews,et al.  Fijianolides, polyketide heterocycles from a marine sponge , 1988 .

[54]  Melvin J. Yu,et al.  In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. , 2001, Cancer research.

[55]  S. Essack,et al.  The Development of β-Lactam Antibiotics in Response to the Evolution of β-Lactamases , 2001, Pharmaceutical Research.