Combinatorial Chemistry Technology

Transcription

1 ugo Kubinyi, ombinatorial hemistry Technology ugo Kubinyi Germany omepage ugo Kubinyi, ombinatorial Diversity in ature 20 natural amino acids yield 400 dipeptides 8,000 tripeptides... 64,000,000 hexapeptides and, in principle, proteins with MW 30 kd 100 chemically modified amino acids yield e.g. 1,000,000,000,000 hexapeptides, and... 4 nucleic bases encode all organisms!

2 ugo Kubinyi, umber of organic molecules with MW < 500 (,,,, P,, F, l, r, I) or more or less... ugo Kubinyi, Principles of ombinatorial hemistry ombinatorial hemistry generates a multitude of chemically related ( congeneric ) compounds, so-called combinatorial libraries" In the last years, combinatorial chemistry in drug research changed more and more to automated parallel synthesis and parallel purification.

3 ugo Kubinyi, lassical organic synthesis: l Me = Me 3 ombinatorial synthesis: e.g. 50 educts x 20 educts = 1,000 products Multistep combinatorial synthesis: 1 educt x 1 educt = 1 product 2 + l Multicomponent reaction (e.g. Ugi reaction): 2 = 2 e.g. 50 x 20 x 20 educts = 20,000 products = e.g. 50 x 20 x 5 x 200 educts = 1 million products ugo Kubinyi, ombinatorial Library * * uilding blocks with 68 different residues in 10 positions ( 1-10 are 5, 10, 10, 4, 2, 5, 5, 2, 5, and 20 residues) generate a library of 20 million different compounds. onsideration of both steric centers (*) increases this number by a factor of four, i.e. to 80 million different compounds.

4 ugo Kubinyi, olid ase ynthesis: eads ross-linked polystyrene ( % divinylbenzene) l l l Functionalization of the beads by chloromethylation and further chemical reactions l ugo Kubinyi, Tentagel eads (Polystyrene, Grafted with Polyoxyethylene), app Polymers, Tübingen, Germany

5 ugo Kubinyi, The Principle of olid ase ynthesis immobilization bead (40-80 µm) and linker scaffold with functional groups cleavage three-step synthesis immobilized product product ugo Kubinyi, The ombination of caffolds and uilding locks 3 building blocks 1-3 and 3 building blocks 1-3 yield 9 products In the same manner, 10 x 10 x 10 building blocks yield 1,000 products

6 ugo Kubinyi, "plit and ombine" Method for Library ynthesis ugo Kubinyi, 3 Mixtures with 9 different compounds in each reaction vessel

7 ugo Kubinyi, Linkers: Merrifield and Wang linkers l Merrifield resin Wang resin ("Wang linker") (several steps) 50% TF (product) ugo Kubinyi, Linkers: a) Merrifield Peptide ynthesis l oc- - 2 oc 1) l / 3 2) oc-2 - / DI oc 2 50% TF 2 2 Dipeptide

8 ugo Kubinyi, ther linkers Me Fmoc Me ink acid linker Me protected ink amide linker Me Trityl linker l protected ieber linker Fmoc ugo Kubinyi, afety catch linkers stable labile base + - = : stable Product = 3 : labile - product- 1 2 product- 1 2

9 ugo Kubinyi, Traceless (safety catch) linker stable u(c) Polymer-supported solution phase syntheses Polymeric reagents + reagent - ugo Kubinyi, olid ase-upported ynthesis of (±)-Epibatidine l 1. Me Me 3 u Me 2 T l 3. Me 3 + Me 2 l 6. Me Mesyl-l l l (±) 2 8. Me Et 2 -tu P l 85% (±) endo basic epimerization (±)-Epibatidine (exo:endo = 3:1). J. ooth and J.. odges, J. m. hem. oc. 119, (1997)

10 ugo Kubinyi, olid ase-upported ynthesis of (±)-xomaritidine and (±)-Epimaritidine Me Me Me Me Me 3 + u l 2 2. Me 100 % Me F 3. V. Ley et al., J. hem. oc. Perkin Trans. 1, (1999) I(X 3 ) 2 X = or F Me F 3 2 Me 70 % (±)-Epimaritidine Me Me 2 Me + 3 -Me 4 Me 90 % F 3 Me Et Me Me Me (±)-xomaritidine 100 % 2 / Pd / Me Me % u 4 or il 2 Me 90 % Me Me (F 3 ) 2 99 % ugo Kubinyi, Polymeric scavengers for building blocks, side products and reagents + excess - + X - + X- reagent X - + X side product D X - + X-D

11 ugo Kubinyi, cavenger eagents: Ion Exchange esins, Polymeric cids and ases, Isocyanates, etc. 2 Me + 1 equivalent 1.2 equivalents Me Me 1. l ( ) 2 ugo Kubinyi, esin capture strategy reagent side product D X cleavage X-- - esin capture with an ion exchange resin /Me (mberlite ion exchange resin) atch and release strategy reagent X side product D [ X--] -

12 ugo Kubinyi, atch and release strategy, using a traceless linker 3 usuki coupling release i Me Me ugo Kubinyi, Milestones in the istory of Multicomponent eactions. trecker (1850).. antzsch (1890) P. iginelli (1893) l Mannich (1912)

13 ugo Kubinyi, M. Passerini (1921) T. ucherer (1934) F. singer (1958) I. Ugi (1959) ugo Kubinyi, omplex Molecules from Multicomponent eactions i(ipr) 3 r steps e.g. r. L. chreiber, cience 287, (2000) L. Weber, Drug Discov. today 7, (2002)

14 ugo Kubinyi, The Generation of caffold Diversity 2 2 Me Me 2 (Me) 2 Me L. Weber, Drug Discov. today 7, (2002) ugo Kubinyi, The Generation of caffold Diversity Et Me L. Weber, Q omb. ci. 24, (2005) Three component Ugi reaction

15 ugo Kubinyi, Increasing Diversity of ombinatorial Libraries F courtesy of Drs. M. Mann, W. auer, erono, Geneva ugo Kubinyi, eferences unin, The ombinatorial Index, cademic Press, an Diego, pp, $ 80. Terrett K, ombinatorial hemistry. xford University Press, ew York, pp, $ 29 (in German 264 pp, EU 29). Jung G, ombinatorial hemistry, Wiley-V, Weinheim, pp, EU 149. eck-ickinger G and Weber P, ombinatorial trategies in iology and hemistry, Wiley, pp, $ 35 (in German EU 20). annwarth W and Felder E, ombinatorial hemistry, Wiley-V, Weinheim, pp, EU 149. eneci P, olid-ase ynthesis and ombinatorial Technologies, Wiley-Interscience, ew York, pp, $ 115. Ghose K and Viswanadhan V, ombinatorial Library Design and Evaluation: Principles. oftware Tools, and pplications in Drug Discovery, Marcel Dekker, ew York, pp, $ 195. icolaou K, anko and artwig W, andbook of ombinatorial hemistry. Drugs, atalysts, Materials, Wiley-V, Weinheim, pp, EU 389.