pactamycin and Neoplasms

Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.

Topics: Anti-Bacterial Agents; Benzoquinones; Biological Products; Cell Line, Tumor; Chemistry, Organic; Chemistry, Pharmaceutical; Glycopeptides; Humans; Lactams, Macrocyclic; Macrolides; Multigene Family; Neoplasms; Pactamycin; Peptides; Polyenes; Synthetic Biology; Tetracyclines

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.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Humans; Nanoparticles; Neoplasms; Pactamycin

A total of eight new analogs of pactamycin were prepared and tested alongside pactamycin and three of its natural congeners for antibacterial, anticancer, and antiprotozoal activities. The present study highlights the effects of changing the urea and aniline groups especially with regard to anticancer and antiprotozoal activities.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Antiprotozoal Agents; Bacteria; Bacterial Infections; Cell Line, Tumor; Humans; Malaria, Falciparum; Neoplasms; Pactamycin; Plasmodium falciparum