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Bifunctional scaffolds as templates for synthetic combinatorial libraries

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Summary

A small-molecule synthetic combinatorial library was designed and synthesized that features potential pharmacophores attached to a variety of small cyclic scaffolds. The synthesis of the library involved randomization of three types of building blocks: 20 amino acids, 10 aromatic hydroxy acids and 21 alcohols, totaling a library complexity of 4200 compounds. Mitsunobu polymer-supported etherification was used in the last randomization. The library compounds were attached to beads via an ester-bond linkage enabling both on-bead as well as in-solution screening. When the library was tested against a model target, streptavidin, specific binders were found. The structures of the most active compounds were determined from the fragmentation pattern in MS/MS experiments.

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Abbreviations

DCM:

dichloromethane

DEAD:

diethyl azodicarboxylate

DIAD:

diisopropyl azodicarboxylate

DIC:

diisopropyl carbodiimide

DMF:

dimethylformamide

Fmoc:

fluorenylmethyloxycarbonyl

HOBt:

N-hydroxybenzotriazole

MeOH:

methanol

PPh3 :

triphenylphosphine

t-Bu:

tert-butyl

TFA:

trifluoroacetic acid

TG:

TentaGel-S-OH 130-μm resin

THF:

tetrahydrofuran

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Author notes

  1. Michal Lebl

    Present address: Houghten Pharmaceuticals Inc., 3550 General Atomics Court, 92121, San Diego, CA, USA

Authors and Affiliations

  1. Selectide Corporation, a subsidiary of Hoechst Marion Roussel, 1580 E. Hanley Boulevard, 85737, Tucson, AZ, USA

    Viktor Krchňák, Aleksandra S. Weichsel, Olga Issakova & Michal Lebl

  2. Arizona Cancer Center, Departments of Medicine, Microbiology and Immunology, University of Arizona, College of Medicine, 85724, Tucson, AZ, USA

    Kit S. Lam

Authors
  1. Viktor Krchňák
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  2. Aleksandra S. Weichsel
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  3. Olga Issakova
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  4. Kit S. Lam
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  5. Michal Lebl
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Krchňák, V., Weichsel, A.S., Issakova, O. et al. Bifunctional scaffolds as templates for synthetic combinatorial libraries. Mol Divers 1, 177–182 (1996). https://doi.org/10.1007/BF01544955

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  • DOI: https://doi.org/10.1007/BF01544955

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