uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Microwave-Assisted Synthesis of Weinreb and MAP Aryl Amides via Pd-Catalyzed Heck Aminocarbonylation Using Mo(CO)(6) or W(CO)(6)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2011 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, nr 3, s. 978-981Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A simple and expedient process for the Heck aminocarbonylative synthesis of Weinreb and MAP amide acylating agents, from aryl halides, is reported. This methodology utilizes solid sources of CO making it readily accessible to chemists working in small-scale laboratory applications.

Ort, förlag, år, upplaga, sidor
2011. Vol. 76, nr 3, s. 978-981
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-148925DOI: 10.1021/jo102151uISI: 000286577400027OAI: oai:DiVA.org:uu-148925DiVA, id: diva2:403926
Tillgänglig från: 2011-03-15 Skapad: 2011-03-14 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Ingår i avhandling
1. Discovery of Small Peptides and Peptidomimetics Targeting the Substance P 1-7 Binding Site: Focus on Design, Synthesis, Structure-Activity Relationships and Drug-Like Properties
Öppna denna publikation i ny flik eller fönster >>Discovery of Small Peptides and Peptidomimetics Targeting the Substance P 1-7 Binding Site: Focus on Design, Synthesis, Structure-Activity Relationships and Drug-Like Properties
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Biologically active peptides are important for many physiological functions in the human body and therefore serve as interesting starting points in drug discovery processes. In this work the neuropeptide substance P 1–7 (SP1–7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), which has been demonstrated to reduce neuropathic pain and attenuate opioid withdrawal symptoms in animal models, has been addressed in a medicinal chemistry program with the overall aim of transforming this bioactive peptide into more drug-like compounds. Specific binding sites for this neuropeptide have been detected in the brain and the spinal cord. Interestingly, the smaller neuropeptide endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) also interacts with these binding sites, although 10-fold less efficient.

In this work the structure–activity relationship of SP1–7 and EM-2, regarding their affinity to the SP1–7 binding site was elucidated using alanine scans, truncation, and terminal modifications. The C-terminal part of both peptides, and especially the C-terminal phenylalanine, was crucial for binding affinity. Moreover, the C-terminal functional group should preferably be a primary amide. The truncation studies finally resulted in the remarkable discovery of H-Phe-Phe-NH2 as an equally good binder as the heptapeptide SP1–7. This dipeptide amide served as a lead compound for further studies. In order to improve the drug-like properties and to find a plausible bioactive conformation, a set of rigidified and methylated dipeptides of different stereochemistry, and analogs with reduced peptide character, were synthesized and evaluated regarding binding, metabolic stability and absorption. Small SP1–7 analogs with retained affinity and substantially improved permeability and metabolic stability were identified.

Beside peptide chemistry the synthetic work included the development of a fast and convenient microwave-assisted protocol for direct arylation of imidazoles. Furthermore, microwave-assisted aminocarbonylation using Mo(CO)6 as a solid carbon monoxide source was investigated in the synthesis of MAP amides and for coupling of imidazoles with amino acids.

In a future perspective the present findings, together with the fact that some of the SP1–7 analogs discovered herein have been shown to reproduce the biological effects of SP1-7 in animal studies related to neuropathic pain and opioid dependence, can ultimately have an impact on drug discovery in these two areas.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 88
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 143
Nyckelord
substance P 1-7, peptidomimetics, structure-activity relationship, drug-like properties, phenylalanine, imidazole, MAP aryl amides, carbonylation
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-149480 (URN)978-91-554-8040-0 (ISBN)
Disputation
2011-05-06, B42, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-04-15 Skapad: 2011-03-20 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Fransson, RebeccaOdell, Luke R.Larhed, Mats

Sök vidare i DiVA

Av författaren/redaktören
Fransson, RebeccaOdell, Luke R.Larhed, Mats
Av organisationen
Avdelningen för organisk farmaceutisk kemi
I samma tidskrift
Journal of Organic Chemistry
Farmaceutiska vetenskaper

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 623 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf