Exploring and exploiting biologically relevant chemical space

Current Drug Targets

Volumn 12, Issue 11, 2011, Pages 1531-1546

  Eberhardt, Luc ^a,b   Kumar, Kamal ^a,b   Waldmann, Herbert ^a,b  

^a MAX PLANCK INSTITUTE OF MOLECULAR PHYSIOLOGY   (Germany)

^b TU DORTMUND UNIVERSITY   (Germany)

Author keywords

Biology oriented synthesis; Compound libraries; Diversity oriented synthesis; Drug discovery; Natural products; Small molecules

Indexed keywords

ARTEMISIN; BAVACHROMANOL; BENZOCHROMENE; BENZOXANTHENE; CALICHEAMICIN; CARPANONE; CHROMENE DERIVATIVE; CRYPTOPHYCIN 1; ERIBULIN; FURANODICTIN; GEMTUZUMAB OZOGAMICIN; HALICHONDRIN B; HYDROXYBUTENOLIDE; MELOPHLIN A; MELOPHLIN B; MEVINOLIN; NATURAL PRODUCT; PACLITAXEL; PSEUDOANGUILLOSPORIN A; PSEUDOANGUILLOSPORIN B; PYRIDONE DERIVATIVE; PYRIMIDINE DERIVATIVE; TACROLIMUS; UNCLASSIFIED DRUG; XANTHENE DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ANTIFUNGAL ACTIVITY; ARTICLE; BIOINFORMATICS; DRUG CONFORMATION; DRUG CYTOTOXICITY; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; NONHUMAN; SOLID PHASE SYNTHESIS; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

BIOLOGICAL AGENTS; MOLECULAR STRUCTURE;

EID: 80054052511     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/138945011798109482     Document Type: Article

References (111)

1. Fersht AR. Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding. New-York: W. H. Freeman; 1999.
2. Regine SB, Colin M, Wayne CG. The art and practice of structure- based drug design: a molecular modeling perspective. Med Res Rev 1996; 16(1): 3-50.
3. Dobson CM. Chemical space and biology. Nature 2004; 432(7019): 824-8.
4. Goto S, Okuno Y, Hattori M, Nishioka T, Kanehisa M. LIGAND: database of chemical compounds and reactions in biological pathways. Nucleic Acids Res 2002; 30(1): 402-4.
5. Luria SE, Gould SJ, Singer S. A View of Life. Menlo Park, California: Benjamin/Cummings; 1981.
6. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822): 860-921.
7. Lipinski C, Hopkins A. Navigating chemical space for biology and medicine. Nature 2004; 432(7019): 855-61.
8. Klebe G. Virtual ligand screening: strategies, perspectives and limitations. Drug Discov Today 2006; 11(13-14): 580-94.
9. Willett P. Similarity-based virtual screening using 2D fingerprints. Drug Discov Today 2006; 11(23-24): 1046-53.
10. Rosén J, Gottfries J, Muresan S, Backlund A, Oprea TI. Novel chemical space exploration via natural products. J Med Chem 2009; 52(7): 1953-62.
11. Gullo V, McAlpine J, Lam K, Baker D, Petersen F. Drug discovery from natural products. J Ind Microbiol Biotechnol 2006; 33(7): 523-31.
12. Li JWH, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science 2009; 325(5937): 161-5.
13. Nobili S, Lippi D, Witort E, et al. Natural compounds for cancer treatment and prevention. Pharmacol Res 2009; 59(6): 365-78.
14. Wessjohann LA. Synthesis of natural-product-based compound libraries. Curr Opin Chem Biol 2000; 4(3): 303-9.
15. Waterman PG. Advances in Drug Discovery Techniques. Harvey AL, ed. Chichester: John Wiley & Sons; 1998.
16. Bertels S, Frormann S, Jas G, Bindseil KU. Drug Discovery from Nature. In: Grabley S, Thiericke R, editors. Heidelberg: Springer- Verlag: Berlin; 1999; pp. 72-105.
17. Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007; 70(3): 461-77.
18. Newman DJ. Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 2008; 51(9): 2589-99.
19. Butler MS. Natural products to drugs: natural product derived compounds in clinical trials. Nat Prod Rep 2005; 22(2): 162-95.
20. Ganesan A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol 2008; 12(3): 306-17.
21. Aicher TD, Buszek KR, Fang FG, et al. Total Synthesis of Halichondrin-B and Norhalichondrin-B. J Am Chem Soc 1992; 114(8): 3162-4.
22. Corbett TH, Valeriote FA, Demchik L, et al. Discovery of cryptophycin-1 and BCN-183577: Examples of strategies and problems in the detection of antitumor activity in mice. Invest New Drugs 1997; 15(3): 207-18.
23. Moore RE, Corbett TH, Patterson GML, Valeriote FA. The search for new antitumor drugs from blue-green algae. Curr Pharm Des 1996; 2(3): 317-30.
24. Barrow RA, Hemscheidt T, Liang J, Paik S, Moore RE, Tius MA. Total synthesis of Cryptophycins - revision of the structures of Cryptophycin-a and Cryptophycin-C. J Am Chem Soc 1995; 117(9): 2479-90.
25. Trimurtulu G, Ohtani I, Patterson GML, et al. Total structures of Cryptophycins, potent antitumor depsipeptides from the blue- green-alga nostoc sp strain Gsv-224. J Am Chem Soc 1994; 116(11): 4729-37.
26. Smith CD, Zhang XQ, Mooberry SL, Patterson GML, Moore RE. Cryptophycin - a new antimicrotubule agent active against drug- resistant cells. Cancer Res 1994; 54(14): 3779-84.
27. Panda D, Himes RH, Moore RE, Wilson L, Jordan MA. Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1. Biochemistry 1997; 36(42): 12948-53.
28. Smith AB, Cho YS, Pettit GR, Hirschmann R. Design, synthesis, and evaluation of azepine-based cryptophycin mimetics. Tetrahedron 2003; 59(35): 6991-7009.
29. Damle NK, Frost P. Anti body-targeted chemotherapy with immunoconjugates of calicheamicin. Curr Opin Pharm 2003; 3(4): 386-90.
30. Hamann PR, Hinman LM, Hollander I, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody- calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconj Chem 2002; 13(1): 47-58.
31. Kumar K, Waldmann H. Synthesis of natural product inspired compound collections. Angew Chem Int Ed 2009; 48(18): 3224-42.
32. Cordier C, Morton D, Murrison S, Nelson A, O'Leary-Steele C. Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries. Nat Prod Rep 2008; 25(4): 719-37.
33. Schreiber SL. The small-molecule approach to biology. Chem Eng News 2003; 81(9): 51-61.
34. Burke MD, Schreiber SL. A planning strategy for diversity- oriented synthesis. Angew Chem Int Ed Engl 2004; 43(1): 46-58.
35. Wilk W, Zimmermann TJ, Kaiser M, Waldmann H. Principles, implemenation and application of biology-oriented synthesis (BIOS). Biol Chem 2010; 391(5): 491-7.
36. Kumar K. Compound Collection Synthesis for Chemical Biology, in: Chemical Biology - Learning through Case Studies. In: Waldmann H, Jenning P, Eds. Weinheim: Wiley-VCH. pp. 39-53.
37. Kumar K, Wetzel S, Waldmann H. Biology Oreinted Synthesis and Diversity Oriented Synthesis in Compound Collection Development, in: The Practice of Medicinal Chemistry. Wermuth CG, ed. 2nd ed: Academic Press; 2008: pp. 187-206.
38. Hafez HN, Hegab MI, Ahmed-Farag IS, El-Gazzar ABA. A facile regioselective synthesis of novel spiro-thioxanthene and spiro- xanthene-9 ',2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents. Bioorg Med Chem Lett 2008; 18(16): 4538-43.
39. Poupelin JP, Saintruf G, Foussardblanpin O, Narcisse G, Uchidaernouf G, Lacroix R. Synthesis and anti-inflammatory properties of bis-(2-hydroxy-1-naphthyl)-methane derivatives. Eur J Med Chem 1978; 13(1): 67-71.
40. Kumar A, Sharma S, Maurya RA, Sarkar J. Diversity oriented synthesis of benzoxanthene and benzochromene libraries via one- pot, three-component reactions and their anti-proliferative activity. J Comb Chem 2010; 12(1): 20-4.
41. Varaprasad CVNS, Ramasamy KS, Girardet JL, et al. Synthesis of pyrrolo[2,3-d]pyrimidine nucleoside derivatives as potential anti- HCV agents. Bioorg Chem 2007; 35(1): 25-34.
42. Cai ZW, Wei D, Schroeder GM, et al. Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors. Bioorg Med Chem Lett 2008; 18(11): 3224-9.
43. Palmer AM, Munch G, Brehm C, et al. 5-Substituted 1H- pyrrolo[3,2-b]pyridines as inhibitors of gastric acid secretion. Bioorg Med Chem 2008; 16(3): 1511-30.
44. Gillespie RJ, Cliffe IA, Dawson CE, et al. Antagonists of the human adenosine A(2A) receptor. Part 3: design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d] pyrimidines and 6- arylpurines. Bioorg Med Chem Lett 2008; 18(9): 2924-9.
45. Taylor EC, Liu B. A new and efficient synthesis of pyrrolo[2,3- d]pyrimidine anticancer agents: Alimta (LY231514, MTA), homo- Alimta, TNP-351, and some aryl 5-substituted pyrrolo[2,3- d]pyrimidines. J Org Chem 2003; 68(26): 9938-47.
46. Gangjee A, Yang J, McGuire JJ, Kisliuk RL. Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates. Bioorg Med Chem 2006; 14(24): 8590-8.
47. Gangjee A, Li W, Yang J, Kisliuk RL. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo- 5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J Med Chem 2008; 51(1): 68-76.
48. Gibson CL, Huggan JK, Kennedy A, et al. Diversity oriented syntheses of fused pyrimidines designed as potential antifolates. Org Biomol Chem 2009; 7(9): 1829-42.
49. Sohly HN, Joshi AS, Nimrod AC, Walker LA, Clark AM. Antifungal chalcones from Maclura tinctoria. Planta Medica 2001; 67(1): 87-9.
50. Tezuka Y, Gewali MB, Ali MS, Banskota AH, Kadota S. Eleven novel diarylheptanoids and two unusual diarylheptanoid derivatives from the seeds of Alpinia blepharocalyx. J Nat Prod 2001; 64(2): 208-13.
51. Hepworth J. Comprehensive Heterocyclic Chemistry. Katritzky AR, Rees CW, editors. Oxford: Elsevier Science; 1984.
52. Römpp-Lexikon Naturstoffe. Stuttgart: Fugmann B; 1997.
53. Seo EK, Wani MC, Wall ME, et al. New bioactive aromatic compounds from Vismia guianensis. Phytochemistry 2000; 55(1): 35-42.
54. Singh IP, Hayakawa R, Etoh H, Takasaki M, Konoshima T. Grandinal, a new phloroglucinol dimer from Eucalyptus grandis. Bioscience Biotech Biochem 1997; 61(5): 921-3.
55. Asai F, Iinuma M, Tanaka T, Mizuno M. Complex flavonoids in farinose exudate from pityrogramma-calomelanos. Phytochemistry 1991; 30(9): 3091-3.
56. Conserva LM, Yoshida M, Gottlieb OR, Martinez JC, Gottlieb HE. The chemistry of colombian myristicaceae.11. Iryantherins, lignoflavonoids of novel structural types from the myristicaceae. Phytochemistry 1990; 29(12): 3911-8.
57. Kock I, Draeger S, Schulz B, et al. Pseudoanguillosporin A and B: two new isochromans isolated from the endophytic fungus pseudoanguillospora sp. Eur J Org Chem 2009; 9: 1427-34.
58. Alvey L, Prado S, Huteau V, et al. A new synthetic access to furo[3,2-f]chromene analogues of an antimycobacterial. Bioorg Med Chem 2008; 16(17): 8264-72.
59. Prado S, Janin YL, Bost PE. Simple two steps ytterbium triflatecatalysed preparation of 2,2-dimethyl-2H-chromenes from salicylaldehydes and 2-methylpropene. J Heterocycl Chem 2006; 43(6): 1605-8.
60. Prado S, Janin YL, Saint-Joanis B, et al. Synthesis and antimycobacterial evaluation of benzofurobenzopyran analogues. Bioorg Med Chem 2007; 15(5): 2177-86.
61. Prado S, Toum Vr, Saint-Joanis B, et al. Antimycobacterial Benzofuro[3,2-f]chromenes from a 5-Bromochromen-6-ol. Synthesis 2007; 2007(10): 1566-70.
62. Janin YL. Antituberculosis drugs: ten years of research. Bioorg Med Chem 2007; 15(7): 2479-513.
63. Prado S, Ledeit H, Michel S, et al. Benzofuro[3,2-f][1]benzopyrans: a new class of antitubercular agents. Bioorg Med Chem 2006; 14(15): 5423-8.
64. Alvey L, Prado S, Saint-Joanis B, et al. Diversity-oriented synthesis of furo[3,2-f]chromanes with antimycobacterial activity. Eur J Med Chem 2009; 44(6): 2497-505.
65. Palomino JC, Martin A, Camacho M, Guerra H, Swings J, Portaels F. Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002; 46(8): 2720-2.
66. Niaura R, Jones C, Kirkpatrick P. Varenicline. Nat Rev Drug Discov 2006; 5(7): 537-8.
67. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha 4 beta 2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005; 48(10): 3474-7.
68. Nören-Müller A, Wilk W, Saxena K, Schwalbe H, Kaiser M, Waldmann H. Discovery of a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B by biology-oriented synthesis. Angew Chem Int Ed 2008; 47(32): 5973-7.
69. Anderson DJ, Arneric SP. Nicotinic receptor-binding of [H-3] Cytisine, [H-3] Nicotine and [H-3] Methylcarbamylcholine in ratbrain. Eur J Pharm 1994; 253(3): 261-7.
70. Jensen AA, Frolund B, Lijefors T, Krogsgaard-Larsen P. Neuronal nicotinic acetylcholine receptors: Structural revelations, target identifications, and therapeutic inspirations. J Med Chem 2005; 48(15): 4705-45.
71. Marcaurelle LA, Johannes C, Yohannes D, Tillotson BP, Mann D. Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2. Bioorg Med Chem Lett 2009; 19(9): 2500-3.
72. Ryba TD, Depew KM, Marcaurelle LA. Large scale preparation of silicon-functionalized synphase polystyrene lanterns for solidphase synthesis. J Comb Chem 2009; 11(1): 110-6.
73. Hotha S, Yarrow JC, Yang JG, et al. HR22C16: a potent smallmolecule probe for the dynamics of cell division. Angew Chem Int Ed 2003; 42(21): 2379-82.
74. Goess BC, Hannoush RN, Chan LK, Kirchhausen T, Shair MD. Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors. J Am Chem Soc 2006; 128(16): 5391-403.
75. Prakesch M, Denisov AY, Naim M, Gehring K, Arya P. The discovery of small molecule chemical probes of Bcl-X-L and Mcl1. Bioorg Med Chem 2008; 16(15): 7443-9.
76. Grishin NV. Fold change in evolution of protein structures. J Struct Biol 2001; 134(2-3): 167-85.
77. Nören-Müller A, Reis-Correa I Jr., Prinz H, et al. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc Natl Acad Sci USA 2006; 103(28): 10606-11.
78. Koch MA, Schuffenhauer A, Scheck M, et al. Charting biologically relevant chemical space: a structural classification of natural products (SCONP). Proc Natl Acad Sci USA 2005; 102(48): 17272-7.
79. Wetzel S, Schuffenhauer A, Roggo S, Ertl P, Waldmann H. Cheminformatic analysis of natural products and their chemical space. Chimia 2007; 61(6): 355-60.
80. Wetzel S, Klein K, Renner S, et al. Interactive exploration of chemical space with Scaffold Hunter. Nat Chem Biol 2009; 5(8): 581-3.
81. Renner S, van Otterlo WA, Dominguez Seoane M, et al. Bioactivity-guided mapping and navigation of chemical space. Nat Chem Biol 2009; 5(8): 585-92.
82. Pettit GR, Cichacz ZA, Gao F, et al. Antineoplastic Agents.257. Isolation and structure of Spongistatin-1. J Org Chem 1993; 58(6): 1302-4.
83. Barun O, Sommer S, Waldmann H. Asymmetric solid-phase synthesis of 6,6-spiroketals. Angew Chem Int Ed Engl 2004; 43(24): 3195-9.
84. Barun O, Kumar K, Sommer S, et al. Natural product-guided synthesis of a spiroacetal collection reveals modulators of tubulin cytoskeleton integrity. Eur J Org Chem 2005; 22): 4773-88.
85. Sommer S, Waldmann H. Solid phase synthesis of a spiro[5.5]ketal library. Chem Commun 2005; 45: 5684-6.
86. Sommer S, Kuhn M, Waldmann H. Solid-phase synthesis of [5.5] spiroketals. Adv Syn Cat 2008; 350(11-12): 1736-50.
87. Correa IR, Jr., Noren-Muller A, Ambrosi HD, et al. Identification of inhibitors for mycobacterial protein tyrosine phosphatase B (MptpB) by biology-oriented synthesis (BIOS). Chem Asian J 2007; 2(9): 1109-26.
88. Koch MA, Wittenberg LO, Basu S, et al. Compound library development guided by protein structure similarity clustering and natural product structure. Proc Natl Acad Sci USA 2004; 101(48): 16721-6.
89. Robinson-Rechavi M, Garcia HE, Laudet V. The nuclear receptor superfamily. J Cell Sci 2003; 116(4): 585-6.
90. Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 2004; 3(11): 950-64.
91. Jordan VC. Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell 2004; 5(3): 207-13.
92. de la Lastra CA, Sanchez-Fidalgo S, Villegas I, Motilva V. New pharmacological perspectives and therapeutic potential of PPARgamma agonists. Curr Pharm Des 2004; 10(28): 3505-24.
93. Dang ZC, Audinot V, Papapoulos SE, Boutin JA, Lowik CWGM. Peroxisome proliferator-activated receptor gamma (PPAR gamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 2003; 278(2): 962-7.
94. Gaal LV, Scheen AJ. Are all glitazones the same? Diabetes/ Metabolism Res Rev 2002; 18: S1-S4.
95. Nicolaou KC, Evans RM, Roecker AJ, Hughes R, Downes M, Pfefferkorn JA. Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries. Org Biomol Chem 2003; 1(6): 908-20.
96. Nicolaou KC, Pfefferkorn JA, Roecker AJ, Cao GQ, Barluenga S, Mitchell HJ. Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans. J Am Chem Soc 2000; 122(41): 9939-53.
97. Nicolaou KC, Pfefferkorn JA, Mitchell HJ, et al. Natural productlike combinatorial libraries based on privileged structures. 2. construction of a 10 000-membered benzopyran library by directed split-and-pool chemistry using NanoKans and optical encoding. J Am Chem Soc 2000; 122(41): 9954-67.
98. Gunasekera SP, McCarthy PJ, KellyBorges M, Lobkovsky E, Clardy J. Dysidiolide: A novel protein phosphatase inhibitor from the Caribbean sponge Dysidea etheria de Laubenfels. J Am Chem Soc 1996; 118(36): 8759-60.
99. Mamane V, Garcia AB, Umarye JD, Lessmann T, Sommer S, Waldmann H. Stereoselective allylation of aldehydes on solid support and its application in biology-oriented synthesis (BIOS). Tetrahedron 2007; 63(26): 5754-67.
100. Garcia AB, Lessmann T, Umarye JD, Mamane V, Sommer S, Waldmann H. Stereocomplementary synthesis of a natural product- derived compound collection on a solid phase. Chem Commun (Camb) 2006; 37: 3868-70.
101. Umarye JD, Lessmann T, Garcia AB, Mamane V, Sommer S, Waldmann H. Biology-oriented synthesis of stereochemically diverse natural-product-derived compound collections by iterative allylations on a solid support. Chem Eur J 2007; 13(12): 3305-19.
102. Lessmann T, Leuenberger MG, Menninger S, et al. Natural product-derived modulators of cell cycle progression and viral entry by enantioselective oxa Diels-Alder reactions on the solid phase. Chem Biol 2007; 14(4): 443-51.
103. Sanz MA, Voigt T, Waldmann H. Enantioselective catalysis on the solid phase: synthesis of natural product-derived tetrahydropyrans employing the enantioselective oxa-Diels-Alder reaction. Adv Synth Cat 2006; 348(12-13): 1511-5.
104. Aoki S, Higuchi K, Ye Y, Satari R, Kobayashi M. Melophlins A and B, novel tetramic acids reversing the phenotype of rastransformed cells, from the marine sponge Melophlus sarassinorum. Tetrahedron 2000; 56(13): 1833-6.
105. Knoth T, Warburg K, Katzka C, et al. The ras pathway modulator melophlin a targets dynamins. Angew Chem Int Ed 2009; 48(39): 7240-5.
106. Walther T, Renner S, Waldmann H, Arndt HD. Synthesis and structure-activity correlation of a brunsvicamide-inspired cyclopeptide collection. Chembiochem 2009; 10(7): 1153-62.
107. Walther T, Arndt HD, Waldmann H. Solid-support based total synthesis and stereochemical correction of brunsvicamide A. Org Lett 2008; 10(15): 3199-202.
108. Waldmann H, Hu TS, Renner S, et al. Total synthesis of chondramide C and its binding mode to F-actin. Angew Chem Int Ed 2008; 47(34): 6473-7.
109. Tannert R, Milroy LG, Ellinger B, Hu TS, Arndt HD, Waldmann H. Synthesis and structure-activity correlation of natural-product inspired cyclodepsipeptides stabilizing F-actin. J Am Chem Soc 2010; 132(9): 3063-77.
110. Lessmann T, Waldmann H. Enantioselective synthesis on the solid phase. Chem Commun (Camb) 2006; 32: 3380-9.
111. Nandy JP, Prakesch M, Khadem S, Reddy PT, Sharma U, Arya P. Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries. Chem Rev 2009; 109(5): 1999-2060.