Part I. Application of 2-Hydroxymethylacrylic Acid, a Product of Baylis-Hillman Reaction, for the Synthesis of Novel N-backbone-to-Side-Chain Cyclic Peptide Analogs: Strategies and Side Reactions Part II. Synthesis and Biological Activities of Chimeric Bioactive Peptides Featuring Amino Acids Coupled to 4-Anilino-N-Phenethyl-Piperidine

Persistent Link:
http://hdl.handle.net/10150/194330
Title:
Part I. Application of 2-Hydroxymethylacrylic Acid, a Product of Baylis-Hillman Reaction, for the Synthesis of Novel N-backbone-to-Side-Chain Cyclic Peptide Analogs: Strategies and Side Reactions Part II. Synthesis and Biological Activities of Chimeric Bioactive Peptides Featuring Amino Acids Coupled to 4-Anilino-N-Phenethyl-Piperidine
Author:
Petrov, Ravil Rashitovich
Issue Date:
2007
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
During my research career in Prof. V.J.Hruby's laboratory I worked on two different projects. The first project, which was initiated by the author, was planned to serve the need of our laboratory for a novel method of peptide cyclization. This method was planned to use recent advances in Pd0-catalyzed asymmetric synthesis combined with the structural richness offered by the Baylis-Hillman chemistry which could open new ways to diverse areas of drug design, molecular immunology and chemotherapy. This approach would provide cyclic peptides featuring N-alkylated amino acids that would confer high resistance to degradation by proteases. Because of numerous synthetic problems imposed, this strategy was not of considerable current use in peptide synthesis, especially on solid supports. However, despite a substantial amount of effort invested, this method faced serious drawbacks such as multistep synthesis and side reactions when applied to solid supports. Moreover, recent introduction of microwave technology which has helped to solve a great number of problems has led to a renaissance in the classical lactam and thioester bond cyclizations which overshadowed our quest for a novel methodology. The second project was focused on application of 4-anilidopiperidines for the synthesis of chimeric bioactive peptides. It was an effort towards the development of novel analgesics with reduced toxicity and enhanced potency. This project linked small molecule and multimeric ligand designs that were ongoing in our laboratory at the time. Major accomplishments in this project were made possible by successful resolution of several research challenges. I was able to find a straightforward, convenient and economical approach for the synthesis of novel analogues on a solid support. These developments led to novel compounds which showed substantial increases in their binding affinity relative to corresponding opioid analogues. To illustrate, compounds PET25, 26, 27, 29, 30, 31, and 32 showed high bioactivity and sub-nanomolar binding affinity to opioid receptors. Most of the peptides generated in the second project are still being investigated for their biological activities by our colleagues at the Department of Pharmacology, but the results to date indicate that some highly potent novel compounds have been made.
Type:
text; Electronic Dissertation
Keywords:
fentanyl derivatives; opioid peptides; Baylis-Hillman reaction; enkephalin analogues; antihyperalgesia; allodynia
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.
Committee Chair:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titlePart I. Application of 2-Hydroxymethylacrylic Acid, a Product of Baylis-Hillman Reaction, for the Synthesis of Novel N-backbone-to-Side-Chain Cyclic Peptide Analogs: Strategies and Side Reactions Part II. Synthesis and Biological Activities of Chimeric Bioactive Peptides Featuring Amino Acids Coupled to 4-Anilino-N-Phenethyl-Piperidineen_US
dc.creatorPetrov, Ravil Rashitovichen_US
dc.contributor.authorPetrov, Ravil Rashitovichen_US
dc.date.issued2007en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractDuring my research career in Prof. V.J.Hruby's laboratory I worked on two different projects. The first project, which was initiated by the author, was planned to serve the need of our laboratory for a novel method of peptide cyclization. This method was planned to use recent advances in Pd0-catalyzed asymmetric synthesis combined with the structural richness offered by the Baylis-Hillman chemistry which could open new ways to diverse areas of drug design, molecular immunology and chemotherapy. This approach would provide cyclic peptides featuring N-alkylated amino acids that would confer high resistance to degradation by proteases. Because of numerous synthetic problems imposed, this strategy was not of considerable current use in peptide synthesis, especially on solid supports. However, despite a substantial amount of effort invested, this method faced serious drawbacks such as multistep synthesis and side reactions when applied to solid supports. Moreover, recent introduction of microwave technology which has helped to solve a great number of problems has led to a renaissance in the classical lactam and thioester bond cyclizations which overshadowed our quest for a novel methodology. The second project was focused on application of 4-anilidopiperidines for the synthesis of chimeric bioactive peptides. It was an effort towards the development of novel analgesics with reduced toxicity and enhanced potency. This project linked small molecule and multimeric ligand designs that were ongoing in our laboratory at the time. Major accomplishments in this project were made possible by successful resolution of several research challenges. I was able to find a straightforward, convenient and economical approach for the synthesis of novel analogues on a solid support. These developments led to novel compounds which showed substantial increases in their binding affinity relative to corresponding opioid analogues. To illustrate, compounds PET25, 26, 27, 29, 30, 31, and 32 showed high bioactivity and sub-nanomolar binding affinity to opioid receptors. Most of the peptides generated in the second project are still being investigated for their biological activities by our colleagues at the Department of Pharmacology, but the results to date indicate that some highly potent novel compounds have been made.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectfentanyl derivativesen_US
dc.subjectopioid peptidesen_US
dc.subjectBaylis-Hillman reactionen_US
dc.subjectenkephalin analoguesen_US
dc.subjectantihyperalgesiaen_US
dc.subjectallodyniaen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.contributor.chairHruby, Victor J.en_US
dc.contributor.committeememberSaavedra, S. Scotten_US
dc.contributor.committeememberGlass, Richard S.en_US
dc.contributor.committeememberMash, Eugene A.en_US
dc.contributor.committeememberYamamura, Henry I.en_US
dc.identifier.proquest2003en_US
dc.identifier.oclc659746598en_US
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