Persistent Link:
http://hdl.handle.net/10150/284265
Title:
Synthesis and molecular modeling study of dolastatin 11 analogues
Author:
Nakkiew, Pichaya
Issue Date:
2000
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:
Nine analogues of dolastatin 11, a potent antineoplastic agent from an Indian Ocean sea hare which interferes with microfilaments, were synthesized, including two natural ones. Although none of these analogues showed stronger activity than dolastatin 11, their syntheses gave better understanding of the structure-activity relationships for dolastatin 11 as described below. The complete lack of activity of the hydroxy acid obtained by hydrolysis of dolastatin 11 showed that the 30-membered ring may be necessary for activity. The high activity of the 3- and 7-nor derivatives showed that the 3- and 7-methyl groups are not needed for strong activity; the former is a drug candidate since it can be prepared pure more economically than dolastatin 11. The synthesis of Ala-epi-dolastatin 11 showed that this stereoisomer has greatly decreased activity, and that it is the persistent by-product in the dolastatin 11 synthesis. Molecular modeling studies showed most of these analogues to have conformations very sin-filar to those of dolastatin 11. However, the very weak activities of the two conformationally-restricted analogues synthesized suggests that none of the three lowest-energy conformations of dolastatin 11 is the binding conformation to F-actin. Two natural analogues isolated from Pacific Ocean blue-green algae were synthesized. The synthesis of the very active majusculamide C confirmed its structure, but the synthesis of the much less active lyngbyastatin 1 showed its configuration in the Ibu unit to have been assigned incorrectly, and that Ibu-epi-dolastatin 12 is a natural product which accompanies it. The broadness of the peaks in the NMR spectra of these two natural products was shown to be due to rotation about their Ibu-Ala amide bonds.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Organic.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Bates, Robert B.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleSynthesis and molecular modeling study of dolastatin 11 analoguesen_US
dc.creatorNakkiew, Pichayaen_US
dc.contributor.authorNakkiew, Pichayaen_US
dc.date.issued2000en_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.abstractNine analogues of dolastatin 11, a potent antineoplastic agent from an Indian Ocean sea hare which interferes with microfilaments, were synthesized, including two natural ones. Although none of these analogues showed stronger activity than dolastatin 11, their syntheses gave better understanding of the structure-activity relationships for dolastatin 11 as described below. The complete lack of activity of the hydroxy acid obtained by hydrolysis of dolastatin 11 showed that the 30-membered ring may be necessary for activity. The high activity of the 3- and 7-nor derivatives showed that the 3- and 7-methyl groups are not needed for strong activity; the former is a drug candidate since it can be prepared pure more economically than dolastatin 11. The synthesis of Ala-epi-dolastatin 11 showed that this stereoisomer has greatly decreased activity, and that it is the persistent by-product in the dolastatin 11 synthesis. Molecular modeling studies showed most of these analogues to have conformations very sin-filar to those of dolastatin 11. However, the very weak activities of the two conformationally-restricted analogues synthesized suggests that none of the three lowest-energy conformations of dolastatin 11 is the binding conformation to F-actin. Two natural analogues isolated from Pacific Ocean blue-green algae were synthesized. The synthesis of the very active majusculamide C confirmed its structure, but the synthesis of the much less active lyngbyastatin 1 showed its configuration in the Ibu unit to have been assigned incorrectly, and that Ibu-epi-dolastatin 12 is a natural product which accompanies it. The broadness of the peaks in the NMR spectra of these two natural products was shown to be due to rotation about their Ibu-Ala amide bonds.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Organic.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.advisorBates, Robert B.en_US
dc.identifier.proquest9992083en_US
dc.identifier.bibrecord.b41167259en_US
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