Templat-basierte Parallelsynthese von Carbonsäureamidbibliotheken; Cyclopentanolamine als chirale Plattform für molekulare Diversität

The main focus of the present studies was the polymer assisted parallel synthesis of lead-like amide libraries. Convergent polymer assistend solution phase (cPASP) strategy allows for the synthesis of a high number of structurally diverse derivates in a comparably short period of time combining conservative synthesis in solution and the use of polymer-bound diversity elements such as carboxylic acids. On the one hand, the desired amino-templates were prepared in solution. On the other hand commercially available carboxylic acid building blocks were immobilized onto a couple&release linker (4-hydroxy-2,3,5,6-tetrafluorobenzoic acid) and onto the Kenner safety-catch linker modified by Ellman, respectively. The final transfer of carboxylic acid equivalents onto the amino-templates yielded the desired amide libraries. These were subsequently probed in terms of biological activity. The main drawback of parallel synthesis in general is that many derivatives that show interesting biological activity are hampered by a high molecular weight. Therefore, as a novel scaffold we focused on chiral 1-aminocyclopentane-2,4-diols because of a low molecular weight, well defined, but variable stereochemistry, and finally a relatively rigid core. In contrast thereto, in the most reported cases the core components have been relatively large. Given that the upper size limit for an effective drug molecule is generally considered to be lower than 500g/mol (Lipinski´s rule of five), substituent size and diversity become severely limited. 1-Amino-cyclopentane-2,4-diols provide an excellent platform to tailor molecular diversity by appending desired substituents at selected positions around the central scaffold. The low molecular weight and the limited number of rotatable bonds render these molecules attractive starting points for drug discovery. The synthesis of the amide derivatives was performed in nine steps. In the course of the synthesis three functionalized centres were obtained. The demanded amino-templates were received after separating the diastereomeric mixture using preparative separation techniques. The presence of three functionalized and stereo-controlled centres on the racemic 1-amino-cyclopentane-2,4-diol scaffolds gives the chemist plenty of scope to custom design molecules to a pharmacophore model or produce lead-like libraries at random. Furthermore other, leadstructure based amino-templates were synthesized and decorated with suitable substituents. Overall after the preparation of seventeen novel amino-templates, the convergent synthesis protocol lead to the desired amide libraries. The obtained test compounds were subsequently probed in terms of biological activity against human pathogenic protozoa, antiviral activity, cancer cell lines etc.