Metal-Templated Assembly of Cyclopropane-Fused Diazepanones and Diazecanones via exo-trig Nucleophilic Cyclization of Cyclopropenes with Tethered Carbamates

This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/acs.joc.8b02062.A strain-release-driven, cation-templated nucleophilic 7- and 8-exo-trig-cyclization of tethered Boc-protected amines to cyclopropenes is described. The featured reaction proceeds in diastereo- and regioselective fashion and allows for preparation of the corresponding 2,5-diazabicyclo[5.1.0]octan-6-ones and 2,6-diazabicyclo[6.1.0]nonan-7-ones as sole products in high yields. Preliminary studies on anticancer activities of these novel cyclopropane-fused medium heterocycles were performed

Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates Against Drug-Resistant Cancer Cells

Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multi-drug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. We describe a series of 2-aryl-2-(3-indolyl)acetohydroxamic acids, which are active against apoptosis- and multidrug-resistant cancer cells as well as glioblastoma neurosphere stem-like cell cultures derived from patients. Thus, the described compounds serve as a novel chemical scaffold for the development of potentially highly effective clinical cancer drugs

Fate, Transformation, and Toxicological Impacts of Pharmaceutical and Personal Care Products in Surface Waters

With the growth of the human population, a greater quantity of pharmaceutical and personal care products (PPCPs) have been released into the environment. Although research has addressed the levels and the impact of PPCPs in the environment, the fate of these compounds in surface waters is neither well known nor characterized. In the environment, PPCPs can undergo various transformations that are critically dependent on environmental factors such as solar radiation and the presence of soil particles. Given that the degradation products of PPCPs are poorly characterized, these “secondary residues” can be a significant environmental health hazard due to their drastically different toxicologic effects when compared with the parent compounds. To better understand the fate of PPCPs, we studied the degradation of selected PPCPs, including ibuprofen and clofibric acid, in aqueous solutions that contained kaolinite clay and were irradiated with a solar simulator. The most abundant degradation products were identified and assessed for their toxicologic impact on selected microorganisms. The degraded mixtures showed lower toxicity than the starting compounds; however, as these degradation products are capable of further transformation and interaction with other PPCPs in natural waters, our work highlights the importance of additionally characterizing the PPCP degradation products

Expanding our Understanding of Sequence-Function Relationships of Type II Polyketide Biosynthetic Gene Clusters: Bioinformatics-Guided Identification of Frankiamicin A from <i>Frankia</i> sp. EAN1pec

<div><p>A large and rapidly increasing number of unstudied “orphan” natural product biosynthetic gene clusters are being uncovered in sequenced microbial genomes. An important goal of modern natural products research is to be able to accurately predict natural product structures and biosynthetic pathways from these gene cluster sequences. This requires both development of bioinformatic methods for global analysis of these gene clusters and experimental characterization of select products produced by gene clusters with divergent sequence characteristics. Here, we conduct global bioinformatic analysis of all available type II polyketide gene cluster sequences and identify a conserved set of gene clusters with unique ketosynthase α/β sequence characteristics in the genomes of <i>Frankia</i> species, a group of Actinobacteria with underexploited natural product biosynthetic potential. Through LC-MS profiling of extracts from several <i>Frankia</i> species grown under various conditions, we identified <i>Frankia</i> sp. EAN1pec as producing a compound with spectral characteristics consistent with the type II polyketide produced by this gene cluster. We isolated the compound, a pentangular polyketide which we named frankiamicin A, and elucidated its structure by NMR and labeled precursor feeding. We also propose biosynthetic and regulatory pathways for frankiamicin A based on comparative genomic analysis and literature precedent, and conduct bioactivity assays of the compound. Our findings provide new information linking this set of <i>Frankia</i> gene clusters with the compound they produce, and our approach has implications for accurate functional prediction of the many other type II polyketide clusters present in bacterial genomes.</p></div