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

Abstract

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.

The chemistry and biology of natural ribomimetics and related compounds

“…, ethyl or hexyl groups, resulted in a loss of cytotoxicity against several human tumour cell lines. 167 …”

Oxidative allene amination for the synthesis of nitrogen-containing heterocycles

“…Jogyamycin is a member of a small class of other natural products that display similar substitution patterns, including pactamycin, de-6-MSA-pactamycin and TM-026. [120][121][122][123][124][125][126] Jogyamycin exhibits potent antiprotozoal activity against organisms that cause malaria and African sleeping sickness, while pactamycin and its analogs have been reported to display anticancer, antiviral and antimicrobial activities, in addition to antiprotozoal activities. 119 A co-crystal structure of pactamycin bound to a Thermus thermophilus 70S ribosome indicate that the binding site is the 30S subunit; the molecule is believed to function as a universal inhibitor of translocation in a highly conserved region of the ribosome.…”

Total Synthesis of Pactalactam, an Imidazolidinone-Type Pactamycin Analogue

“…Its attractive bioactivity and intriguing chemical structure based on a densely functionalized cyclopentane core drove the isolation of several related bioactive aminocyclitols, such as 7-deoxypactamycin and 8″-hydroxypactamycin, − as well as the recently isolated jogyamycin . Although the development of 1 as a clinical drug has been curtailed by its broad and potent cytotoxicity, these related analogues exhibit antimicrobial, antitumor, and antiprotozoal activities, among others. However, their structure–activity relationships are not completely understood.…”