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Development of Polyamine Lassos as Polyamine Transport Inhibitors

  • Aiste Dobrovolskaite
    Aiste Dobrovolskaite
    Department of Medical Education, College of Medicine, University of Central Florida, Orlando, Florida 32826, United States
  • Richard Andrew Gardner
    Richard Andrew Gardner
    Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, United Kingdom
  • Jean-Guy Delcros
    Jean-Guy Delcros
    Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Small Molecules for Biological Targets Team, Lyon 69373, France
  • , and 
  • Otto Phanstiel IV*
    Otto Phanstiel, IV
    Department of Medical Education, College of Medicine, University of Central Florida, Orlando, Florida 32826, United States
    *Email: [email protected]. Tel: 407-823-6545. Fax: 407-384-2062.
Cite this: ACS Med. Chem. Lett. 2022, 13, 2, 319–326
Publication Date (Web):January 20, 2022
https://doi.org/10.1021/acsmedchemlett.1c00557
Copyright © 2022 American Chemical Society

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    Abstract

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    Nine- and twelve-membered triaza-macrocycles were appended to one end of homospermidine to make polyamine lassos. These compounds were shown to be potent polyamine transport inhibitors (PTIs) using pancreatic ductal adenocarcinoma L3.6pl cells, which have high polyamine transport activity. The smaller triazacyclononane-based lasso significantly reduced the uptake of a fluorescent polyamine probe and inhibited spermidine uptake and reduced intracellular polyamine levels in difluoromethylornithine (DFMO)-treated L3.6pl cells. Both designs were shown to be effective inhibitors of 3H-spermidine uptake, with the smaller lasso outperforming the larger lasso. When the smaller lasso was challenged to inhibit each of the three radiolabeled native polyamines, it had similar Ki values as those of the known PTIs, Trimer44NMe and AMXT1501. Because of these promising properties, these materials may have future anticancer applications in polyamine blocking therapy, an approach that couples a polyamine biosynthesis inhibitor (DFMO) with a PTI to lower intracellular polyamines and suppress cell growth.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00557.

    • Materials, methods for cell growth assays, radiolabeled polyamine and Ant44 uptake assays and intracellular polyamine quantification assays, statistical analysis, synthesis procedures and characterization (1H NMR, 13C NMR, and HRMS) for lasso 6 and lasso 7, synthesis scheme, procedures and characterization (1H NMR, 13C NMR, and HRMS) for tert-butyl-(4-(2-oxo-1,3-oxazinan-3-yl)butyl)carbamate, table of polyamine Km values in L1210 and L3.6pl cells, 1H NMR spectra for compounds 37, 1H COSY spectra for compounds 4, 6, and 7, and 13C NMR spectra for compounds 47 (PDF)

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    Cited By

    This article is cited by 1 publications.

    1. Aiste Dobrovolskaite, Holly Moots, Mukund P. Tantak, Kunal Shah, Jenna Thomas, Sharifa Dinara, Chelsea Massaro, Paul M. Hershberger, Patrick R. Maloney, Satyamaheshwar Peddibhotla, Eliot Sugarman, Sally Litherland, Juan Pablo Arnoletti, Rajiv Kumar Jha, David Levens, Otto Phanstiel, IV. Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function. Journal of Medicinal Chemistry 2022, 65 (22) , 15391-15415. https://doi.org/10.1021/acs.jmedchem.2c01350

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