Abstract

The completion of the total synthesis of deoxybouvardin and bouvardin (NSC 259968), unusual bicyclic hexapeptides possessing confirmed antitumor properties, the total synthesis of structurally-related agents, and the completion of cytotoxic, antitumor, and antimicrobial structure-activity studies including the evaluation of key partial structures are detailed. Extensions of the implemented methodology for peptide diaryl ether formation to the synthetic preparation of isodityrosine and total synthesis of 0F4949 I-IV (aminopeptidase inhibitors with confirmed antitumor and metastatic activity), K-13 (angiotensin I converting enzyme inhibitor) and piperazinomycin are detailed. New studies detailing the total synthesis of the naturally- occurring cyclic decapeptide antitumor-antibiotics luzopeptin -A, -B, -C, and E2 (BBM 928A-C, E2) and the initiation of cytotoxic, antitumor, and antimicrobial structure-activity studies are detailed. Additional studies designed to delineate the structural features of the naturally-occurring B-DNA bisintercalating agents which are responsible for or contribute to the agent B-DNA affinity and sequence-selectivity (bisintercalation and complementary peptide minor groove association) will be pursued.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA041101-07
Application #
3181415
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1985-07-01
Project End
1992-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Wu, Zhi-Chen; Isley, Nicholas A; Boger, Dale L (2018) N-Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification. ACS Infect Dis 4:1468-1474
Okano, Akinori; Isley, Nicholas A; Boger, Dale L (2017) Peripheral modifications of [?[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Proc Natl Acad Sci U S A 114:E5052-E5061
Okano, Akinori; Isley, Nicholas A; Boger, Dale L (2017) Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues. Chem Rev 117:11952-11993
Boger, Dale L (2017) The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface. J Org Chem 82:11961-11980
Okano, Akinori; Nakayama, Atsushi; Wu, Kejia et al. (2015) Total syntheses and initial evaluation of [?[C(?S)NH]Tpg?]vancomycin, [?[C(?NH)NH]Tpg?]vancomycin, [?[CH?NH]Tpg?]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antib J Am Chem Soc 137:3693-704
Lee, Kiyoun; Poudel, Yam B; Glinkerman, Christopher M et al. (2015) Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs. Tetrahedron 71:5897-5905
Hou, L; Jiang, J; Liu, B et al. (2014) Association between smoking and deaths due to colorectal malignant carcinoma: a national population-based case-control study in China. Br J Cancer 110:1351-8
Okano, Akinori; Nakayama, Atsushi; Schammel, Alex W et al. (2014) Total synthesis of [?[C(?NH)NH]Tpg(4)]vancomycin and its (4-chlorobiphenyl)methyl derivative: impact of peripheral modifications on vancomycin analogues redesigned for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J Am Chem Soc 136:13522-5
Nakayama, Atsushi; Okano, Akinori; Feng, Yiqing et al. (2014) Enzymatic glycosylation of vancomycin aglycon: completion of a total synthesis of vancomycin and N- and C-terminus substituent effects of the aglycon substrate. Org Lett 16:3572-5
Pinchman, Joseph R; Boger, Dale L (2013) Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues. J Med Chem 56:4116-24

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