Probing functional diversity in pactamycin toward antibiotic, antitumor, and antiprotozoal activity

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.

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Section: Introductionmentioning

confidence: 99%

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

Sharpe

Malinowski

Sorana

et al. 2015

Bioorganic & Medicinal Chemistry

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“…18 This tactic proved effective in the preparation of a series of functionalized ureas in good yields. 19 By contrast, our synthesis of 1 utilized an early-stage N-H insertion reaction to install the urea. 20 Synthetic diversification from this early intermediate would be a significant challenge.…”

Section: C1-dimethylureamentioning

confidence: 99%

“…These results, in combination with those of the pactamycin C3 analogs, speak to the importance of the macetyl functionality in 1 to its bioactivity. 22 The results of compounds bearing diversity at C5 are shown in entries [16][17][18][19]. In combination with the C5 derivatives previously described (vide supra), an additional derivative 29 (entry 19) was prepared bearing alternate functionality at the C3 aniline for comparison (see Supporting information).…”

Section: Biological Evaluationmentioning

confidence: 99%

“…18,19 We were encouraged by the aniline flexibility demonstrated by Hanessian in their earlier report and hoped that epoxide 11 would participate in related transformations with functionally and electronically diverse anilines.…”

Section: C3-anilinementioning

confidence: 99%

“…18 Since this initial publication, Hanessian has demonstrated the efficacy of his route to deliver pactamycin derivatives at the C1-dimethylurea and the C3 aniline positions such as compounds 7 and 8. 19 Our group began work on the total synthesis of 1 in 2009, and this work culminated in 2013 with a 15-step, asymmetric synthesis from commercially available 2,4-pentanedione (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

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Preparation and Biological Evaluation of Synthetic and Polymer-Encapsulated Congeners of the Antitumor Agent Pactamycin: Insight into Functional Group Effects and Biological Activity

Sharpe

2016

Stereoselective Desymmetrization Methods in the Assembly of Complex Natural Molecules

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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-ofconcept, 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.

show abstract

Hybrids, Congeners, Mimics, and Constrained Variants Spanning 30 Years of Natural Products Chemistry: A Personal Retrospective

Hanessian

2014

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Probing functional diversity in pactamycin toward antibiotic, antitumor, and antiprotozoal activity

Cited by 30 publications

References 30 publications

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

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

Preparation and Biological Evaluation of Synthetic and Polymer-Encapsulated Congeners of the Antitumor Agent Pactamycin: Insight into Functional Group Effects and Biological Activity

Hybrids, Congeners, Mimics, and Constrained Variants Spanning 30 Years of Natural Products Chemistry: A Personal Retrospective

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