Target-oriented and diversity-oriented organic synthesis in drug discovery.

Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

[1]  Eduard Farber.  The Evolution Of Chemistry: A History Of Its Ideas, Methods, And Materials , 1952 .

[2]  R. B. Merrifield.  Solid phase peptide synthesis. I. the synthesis of a tetrapeptide , 1963 .

[3]  Sewall Wright,et al.  Evolution and the Genetics of Populations. I, Genetic and Biometric Foundations. , 1969 .

[4]  H. Rapoport,et al.  Cyclization via solid phase synthesis. Unidirectional Dieckmann products from solid phase and benzyl triethylcarbinyl pimelates , 1970 .

[5]  J. Font,et al.  Organic syntheses with functionalized polymers: I. Preparation of polymeric substrates and alkylation of esters. , 1971 .

[6]  C. Leznoff,et al.  The Use of Polymer Supports in Organic Synthesis. The Synthesis of Monotrityl Ethers of Symmetrical Diols , 1972 .

[7]  J. V. Nelson,et al.  Stereochemical study of the [3,3] sigmatropic rearrangement of 1,5-diene-3-alkoxides. Application to the stereoselective synthesis of (.+-.)-juvabione , 1980 .

[8]  Steven H. Bertz,et al.  Convergence, molecular complexity, and synthetic analysis , 1982 .

[9]  R. Frank,et al.  A new general approach for the simultaneous chemical synthesis of large numbers of oligonucleotides: segmental solid supports , 1983, Nucleic Acids Res..

[10]  H. M. Geysen,et al.  Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Houghten.  General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Á. Furka,et al.  General method for rapid synthesis of multicomponent peptide mixtures. , 2009, International journal of peptide and protein research.

[13]  R. Houghten,et al.  Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery , 1991, Nature.

[14]  K. Lam,et al.  A new type of synthetic peptide library for identifying ligand-binding activity , 1992, Nature.

[15]  L Wang,et al.  Peptoids: a modular approach to drug discovery. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Barry A. Bunin,et al.  A general and expedient method for the solid-phase synthesis of 1,4-benzodiazepine derivatives , 1992 .

[17]  R. Zuckermann,et al.  Encoded combinatorial peptide libraries containing non-natural amino acids , 1993 .

[18]  M. Wigler,et al.  Complex synthetic chemical libraries indexed with molecular tags. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Schroeder,et al.  "Diversomers": an approach to nonpeptide, nonoligomeric chemical diversity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  T. Huynh-Dinh,et al.  The logic of chemical synthesis , 1996 .

[21]  Harry C. J. Ottenheijm,et al.  Solid-phase organic reactions: A review of the recent literature , 1996 .

[22]  K. E. Newhouse.  Goodman and Gilman's The Pharmacological Basis of Therapeutics , 1986, The Yale Journal of Biology and Medicine.

[23]  R. Grubbs,et al.  Tandem Ring Opening−Ring Closing Metathesis of Cyclic Olefins , 1996 .

[24]  J M Blaney,et al.  Computational approaches for combinatorial library design and molecular diversity analysis. , 1997, Current opinion in chemical biology.

[25]  Harry C. J. Ottenheijm,et al.  Solid-phase organic reactions II: A review of the literature Nov 95–Nov 96 , 1997 .

[26]  P. Bartlett,et al.  Synthetic strategies in combinatorial chemistry. , 1997, Current opinion in chemical biology.

[27]  Stuart L. Schreiber,et al.  Stereoselective Synthesis of over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays , 1998 .

[28]  D. Heerding,et al.  Combinatorial chemistry. Use of an intramolecular ruthenium catalyzed olefin/alkyne metathesis reaction in tandem with a Diels-Alder cycloaddition reaction to construct functionalized hexahydroisoindoles , 1998 .

[29]  Yusheng Wu,et al.  TOTAL SYNTHESIS OF (+)-NEOCARZINOSTATIN CHROMOPHORE , 1998 .

[30]  W. Ryan,et al.  Automated parallel synthesis of chalcone-based screening libraries , 1998 .

[31]  S. Haggarty,et al.  Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. , 1999, Science.

[32]  R. Dolle,et al.  Comprehensive survey of combinatorial library synthesis: 1998. , 1999, Journal of combinatorial chemistry.

[33]  Bräse,et al.  New Efficient Multicomponent Reactions with C-C Coupling for Combinatorial Application in Liquid and on Solid Phase. , 1999, Angewandte Chemie.

[34]  K. Paulvannan.  Preparation of tricyclic nitrogen heterocycles via tandem four-component condensation/intramolecular Diels-Alder reaction , 1999 .

[35]  S. Schreiber,et al.  A Strategy for Macrocyclic Ring Closure and Functionalization Aimed toward Split-Pool Syntheses , 1999 .

[36]  THE DEVELOPMENT OF A SOLID PHASE TSUGE REACTION AND ITS APPLICATION IN HIGH THROUGHPUT ROBOTIC SYNTHESIS , 1999 .

[37]  S. Schreiber,et al.  Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M V Chernov,et al.  A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. , 1999, Science.

[39]  S. Schreiber,et al.  Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. , 2000, Organic letters.