Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance

Z. Xia, Charles Smith

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either of the transport proteins, P-glycoprotein or MRP1. Because of this activity, methods for the synthesis of analogues of this oxazole- and thiazole-containing cyclic peptide have been developed; and the total synthesis of 1 has been completed. Highlights of the synthetic strategy are as follows: (1) a dicyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction with Burgess reagent and DBU-assisted oxidation to form D-Alaoxazole; (2) formation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reactions; and (3) use of molecular modeling to select the preferred precursor for the final cyclization of the peptide analogue. Synthetic 1 demonstrated spectral properties identical to those of the natural product and reversed P-glycoprotein-mediated drug resistance more effectively than MRP1-mediated resistance. Certain of the synthetic precursors had biological activity, indicating that cell permeability and peptide cyclization are necessary for optimal activity. Thus, the structure and the biological activities of the natural product are confirmed, and methods for the synthesis of analogues for further structure-activity explorations are defined.

Original languageEnglish (US)
Pages (from-to)3459-3466
Number of pages8
JournalJournal of Organic Chemistry
Volume66
Issue number10
DOIs
StatePublished - May 18 2001

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Cyclic Peptides
Thiazoles
Cyclization
P-Glycoprotein
Bioactivity
Biological Products
Oxazoles
Pharmaceutical Preparations
Dicyclohexylcarbodiimide
Peptides
Molecular modeling
Tumors
Carrier Proteins
Cells
Oxidation
dendroamide A

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

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abstract = "Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either of the transport proteins, P-glycoprotein or MRP1. Because of this activity, methods for the synthesis of analogues of this oxazole- and thiazole-containing cyclic peptide have been developed; and the total synthesis of 1 has been completed. Highlights of the synthetic strategy are as follows: (1) a dicyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction with Burgess reagent and DBU-assisted oxidation to form D-Alaoxazole; (2) formation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reactions; and (3) use of molecular modeling to select the preferred precursor for the final cyclization of the peptide analogue. Synthetic 1 demonstrated spectral properties identical to those of the natural product and reversed P-glycoprotein-mediated drug resistance more effectively than MRP1-mediated resistance. Certain of the synthetic precursors had biological activity, indicating that cell permeability and peptide cyclization are necessary for optimal activity. Thus, the structure and the biological activities of the natural product are confirmed, and methods for the synthesis of analogues for further structure-activity explorations are defined.",
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Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. / Xia, Z.; Smith, Charles.

In: Journal of Organic Chemistry, Vol. 66, No. 10, 18.05.2001, p. 3459-3466.

Research output: Contribution to journalArticle

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