I. Development of Bisamides as Kappa Opioid Receptor Agonists. II. Potency Enhancement of Sulfonamide-based Kappa Opioid Receptor Antagonists. III. Asymmetric Acyl Transfer Reactions Catalyzed by a Cyclic Peptide.
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Issue Date
2017-05-31Author
Ma, Huiyong
Publisher
University of Kansas
Format
397 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Medicinal Chemistry
Rights
Copyright held by the author.
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Development of Bisamides as Kappa Opioid Receptor Agonists. The structure-activity relationship (SAR) expansion was carried out on bisamides KOR agonists. Previous four-step linear synthetic route was replaced by Ugi multicomponent reaction, affording final compound in one step. Parallel synthesis was adopted using Bohdan MiniBlock synthesis platform in combination with subsequent purification with MS-directed HPLC. A total of 80 analogues with diverse substitutions were prepared, including three pairs of enantiomers obtained by chiral HPLC separation of racemic precursors. All of the final compounds were tested in [35S]GTPγS functional assay. Enantiopure analogues were also accessed by arrestin2 imaging assay. Several analogues with improved potency and bias toward G-protein signaling were obtained. A useful SAR was established based on the biological results obtained, which would direct the study of this chemotype in future. Potency Enhancement of Sulfonamide-based Kappa Opioid Receptor Antagonists. Structural modification on a sulfonamide-based KOR antagonists was accomplished. A total of 34 analogues were prepared through linker replacement, constraint manipulation, and substitution introduction. All of the final compounds were assayed using a DiscoveRx PathHunter -arrestin assay platform. One compound with four-fold increase of potency (IC50 = 18.9 ± 4 nM) was obtained, compared with the lead compound (IC50 = 83.5 ± 20.3 nM). A putative binding mode of sulfonamide analogues with the KOR were generated based on the data obtained previously and this study. The enriched SAR and putative binding mode provide insights into the interactions between sulfonamide analogues and the KOR which will direct further study on this chemotype. Asymmetric Acyl Transfer Reactions Catalyzed by a Cyclic Peptide. Kinetic resolution of secondary alcohols by a cyclic peptide was described. The cyclic peptide was designed as a modified version of Miller’s peptide catalyst, which was synthesized in five steps. Single crystal X-ray experiments demonstrated that it adopted a conformation close to type II -turn. Selectivity of this proposed catalyst was examined on five secondary alcohols, with best selectivity factor as about 24.
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