O-glycopeptide analogues of enkephalin: FMOC-amino acid glycoside synthesis, solid-phase glycopeptide synthesis and optimizations, and pharmacology

Persistent Link:
http://hdl.handle.net/10150/283920
Title:
O-glycopeptide analogues of enkephalin: FMOC-amino acid glycoside synthesis, solid-phase glycopeptide synthesis and optimizations, and pharmacology
Author:
Mitchell, Scott Allan
Issue Date:
1999
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:
The synthesis of a series of N-9-fluorenylmethoxycarbonyl (N-FMOC) protected amino acid glycosides is reported. These (1-2)-trans glycosides came directly from Koenigs-Knorr type glycosylations under Hanessian's silver triflate conditions, except for the synthesis of N-acetylgalactosamine FMOC amino acid in which silver perchlorate conditions were used to promote α-glycoside formation. The effect of D-amino acid aglycones was investigated under glucosylation conditions, and a yield dependence on amino protection was seen in the enantiomers of threonine. Due to this match vs. mismatch dichotomy, both O'Donnell Schiff bases and FMOC-amino aglycones were used in the subsequent glycosylation reactions. Glycosides were made using the monosaccharides xylose, mannose, glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, and disaccharides lactose [galactose-β-(1-4)-glucose], cellobiose [glucose-β-(1-4)-glucose] and melibiose [galactose-α-(1-6)-glucose]. All glycosides were converted to their respective FMOC-amino acid forms for direct use in solid-phase glycopeptide synthesis (SPGPS) using established methodology. A strategy into the synthesis of an FMOC-amino acid trisaccharide of Lewis ˣ (Leˣ) was also investigated in an effort to expand on the established glycoside methodology. Preliminary work with D-glucosamine and L-fucose is reported. Our synthetic rationale was based on retaining the peptide pharmacophore or message sequence constant as DCDCE (D-cys²ʼ⁵-enkephalin) with a serine-glycine tether, and making changes only in the environment of the amino-acid glycoside. Changes in amino acid, amino acid chirality, and in the sugar moiety itself would provide a stereochemical investigation into the requisite orientation and electronics for optimum blood-brain barrier (BBB) penetration, opiate receptor binding, and analgesia. Several glycopeptides were synthesized, and all were purified in both reduced and oxidized forms (if containing cysteine). A highly optimized glycopeptide synthetic strategy has been developed and will be presented and critiqued. Pharmacological analysis involving serum stability studies, BBB-penetration studies, GPI/MVD physicochemical studies and mu/delta-opiate receptor studies were completed on all glycopeptides. SAM-1095, the most potent of the glycopeptides synthesized, was resynthesized on a large scale, and this compound was assessed for in vivo pharmacology, along with the non-glycosylated version SAM-995. Preliminary results demonstrate an analgesic effect similar to that of the narcotic morphine. Assessment of all pharmacology will afford a platform for future SAR-based glycopeptide investigations.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Organic.; Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Polt, Robin L.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleO-glycopeptide analogues of enkephalin: FMOC-amino acid glycoside synthesis, solid-phase glycopeptide synthesis and optimizations, and pharmacologyen_US
dc.creatorMitchell, Scott Allanen_US
dc.contributor.authorMitchell, Scott Allanen_US
dc.date.issued1999en_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.abstractThe synthesis of a series of N-9-fluorenylmethoxycarbonyl (N-FMOC) protected amino acid glycosides is reported. These (1-2)-trans glycosides came directly from Koenigs-Knorr type glycosylations under Hanessian's silver triflate conditions, except for the synthesis of N-acetylgalactosamine FMOC amino acid in which silver perchlorate conditions were used to promote α-glycoside formation. The effect of D-amino acid aglycones was investigated under glucosylation conditions, and a yield dependence on amino protection was seen in the enantiomers of threonine. Due to this match vs. mismatch dichotomy, both O'Donnell Schiff bases and FMOC-amino aglycones were used in the subsequent glycosylation reactions. Glycosides were made using the monosaccharides xylose, mannose, glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, and disaccharides lactose [galactose-β-(1-4)-glucose], cellobiose [glucose-β-(1-4)-glucose] and melibiose [galactose-α-(1-6)-glucose]. All glycosides were converted to their respective FMOC-amino acid forms for direct use in solid-phase glycopeptide synthesis (SPGPS) using established methodology. A strategy into the synthesis of an FMOC-amino acid trisaccharide of Lewis ˣ (Leˣ) was also investigated in an effort to expand on the established glycoside methodology. Preliminary work with D-glucosamine and L-fucose is reported. Our synthetic rationale was based on retaining the peptide pharmacophore or message sequence constant as DCDCE (D-cys²ʼ⁵-enkephalin) with a serine-glycine tether, and making changes only in the environment of the amino-acid glycoside. Changes in amino acid, amino acid chirality, and in the sugar moiety itself would provide a stereochemical investigation into the requisite orientation and electronics for optimum blood-brain barrier (BBB) penetration, opiate receptor binding, and analgesia. Several glycopeptides were synthesized, and all were purified in both reduced and oxidized forms (if containing cysteine). A highly optimized glycopeptide synthetic strategy has been developed and will be presented and critiqued. Pharmacological analysis involving serum stability studies, BBB-penetration studies, GPI/MVD physicochemical studies and mu/delta-opiate receptor studies were completed on all glycopeptides. SAM-1095, the most potent of the glycopeptides synthesized, was resynthesized on a large scale, and this compound was assessed for in vivo pharmacology, along with the non-glycosylated version SAM-995. Preliminary results demonstrate an analgesic effect similar to that of the narcotic morphine. Assessment of all pharmacology will afford a platform for future SAR-based glycopeptide investigations.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Organic.en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorPolt, Robin L.en_US
dc.identifier.proquest9927459en_US
dc.identifier.bibrecord.b39559889en_US
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