Synthetic Libraries of linear Oligomers

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1 ynthetic Libraries of linear ligomers tephan eiffert Peptides: highly valuable lead structures for drug discovery Peptidomimetics * high ability to bind selectively at a large number of biological receptors (activate or inhibite) Drawback of Peptides: limited by physico-chemical properties e.g. * low bioavailability * rapid enzymatic digestion Aim: ynthetic libraries of sophisticated peptid-similar polymeric frameworks with: * new chemical, conformational and biological properties 1

2 Design of new peptidomimetics: * fundamental importance of the physico-chemical nature of the polymer backbone and the side chains side chain functionalities: *electrostatic *hydrophobic interactions * π-tacking *hydrogen bonding new degrees of freedom in the conformation of the backbone remember: normal peptid backbone 1 2 n 2 C C C C C C * requirement for an efficient, high-yielding coupling reaction on solid support... 2

3 ne Peptide bond modification: Peptoids: made up of -substituted glycine monomers Peculiar characteristics: (i) the peptoid backbone is achiral (ii) no amide protons,which decrease the polarity of the peptids increases oral bioavailability (iii) lack of -donor bond and, therefore, they do not have the possibility to form intra- or intermolecular -bonding through the backbone (iv) more flexible; they can adopt altered conformations (v) only tertiary amide bonds higher protease stability 3

4 1.1 ubmonomer Approach Br 2 DM BrC2C DIC, DMF Br 2 DM 2 *Use of commercially available building blocks bromacetic acid *Efficient *allows molecular diversity of the monomers Ideal for the automated generation of combinatorial libraries creening of a mixture of ca dimer and trimer Gs Dimer peptoid ligand: Potent ligand for the α 1 -adrenergic receptor 2 structural elements like the endogenous ligand epinephrine and norepinephrine 4

5 1.2 Monomer Approach (1992 imon, reinvestigated by Liskamp) * use of preformed Fmoc--protected G residues Fmoc BP/Bt/DIEA MP Fm oc 2 2 Piperidine DMF 2 + Fmoc 3 BP/Bt/DIEA MP Fm oc 3 Large amounts of peptoids of reasonable purity available The progress of each coupling step can be followed Fully automated synthesizer 5

6 1.3 Peptomers (Goodman) * peptide-peptoid hybrids * generation in solution incorparation of peptoid residues in collagenbased sequences and in a selective somatastin analogue (Goodman) - high triple-helix propensity (collagen) - inhibits the release of growth hormone without any effect on insulin(somatastin) 1.4 Peralkylated Peptides (= C α -branched peptoids) Beginning: *post modification of peptide libraries (libraries from libraries) a) solution of sodium hydride in dimethylsulfoxide b) methyl iodide non selektive; all amide bonds are involved ow: *Two chemoselektive -alkylation methods first step: protection of the free amino group with o-b-cl trategy A trategy B 6

7 Protection: 2 2 o-b-cl DCM, Collidine trategy A : C C 3 C 3 C 2 C 2 DBU, DMF C 3 trategy B (eichwein, Liskamp) : 2, DEAD P 3, DCM KtBu, Ph DMF C 3 7

8 ome ther modification classes : 1. ligocarbamates ne Application: * Design of an oligocarbamat to bind TA (trans-activation reponsive region) A, derived from the A-binding Tat peptide, which is involved in the mechanism of trans-activation of IV-I specific binding to TA A with high affinity, forming a 2 complex stable to proteolytic digestion 2. ulfonopeptides and Vinylogous_ulfonamidopeptides *preparation of combinatorial libraries of tweezer-like synthetic receptors attraktive tools to study the structure and interactions of peptidomimetics with peptides, proteins and small molecules Bo c Bo c 3. ligoureas 2 Combinatorial libraries has been tested at opioid receptors compounds with an activity for the σ receptor have been identified 8

9 Many other modifications * Vinylogous Polypeptides * etro-inverso Pseudopeptides * Azatides and Azapeptides * Methylene Ether Isosteres... ummary * intensive efforts have been made to create novel and original synthetic oligomers * Aim: - improved pharmacological properties - new conformational features of new synthetic frameworks - additional information on the structure-activity relationships - indentification of new lead structures is strictly related to the generation of a large number of compounds development of combinatorial chemistry techniques and solid-phase methods is very important for creation of synthetic libraries of linear oligomers 9