Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 8; pp. 1849 - 1857
• Main Authors: Sharpe, Robert J., Malinowski, Justin T., Sorana, Federico, Luft, J. Christopher, Bowerman, Charles J., DeSimone, Joseph M., Johnson, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.04.2015; Elsevier
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Carriers - chemistry; Humans; Life Sciences & Biomedicine; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Pactamycin; Pactamycin - administration & dosage; Pactamycin - analogs & derivatives; Pactamycin - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structural derivatization; Structure activity relationships; Nanoparticles; Pactamycin; Structure activity relationships; Structural derivatization; DESIGN; EFFICACY; CONVERSION; ANALOGS; UNSYMMETRICAL UREAS; PHASE-III TRIAL; PHARMACOKINETICS; BIOSYNTHESIS; DIVERSITY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.02.022

[Display omitted] The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation.