Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A

Abstract

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 μg/mL. The approach is readily adaptable to large-scale synthesis and industrial production.

Site‐Selective C–H Bond Activation/Functionalization of Alpha‐Amino Acids and Peptide‐Like Derivatives

“…The potential of borylation reactions on amino acid derivatives was shown by the extraordinary work of Elhammer et al (Scheme ) . Different analogs of Aureobasidin A ( 45 ), an antifungal agent, were synthesized via the iridium‐catalyzed C–H borylation methodology, followed by iodination and a Suzuki coupling.…”

Sphingolipids as Targets for Treatment of Fungal Infections

“…Discovered in 1995 [109], novel chemistry for the modification of AbA to broaden its spectrum of activity is very promising [111]. In addition to decrease the production of IPCs, AbA treatment results in an accumulation of ceramide to a toxic level [112].…”

Design of a Mestranol 2‐N‐Piperazino‐Substituted Derivative Showing Potent and Selective in vitro and in vivo Activities in MCF‐7 Breast Cancer Models

“…Cancer is still the world's leading cause of disease‐related mortality, and pharmacology improvements leading to novel therapeutics remain a major focus in the medicinal chemistry research community. With this mindset, the development of novel anticancer agents from diverse natural compounds has been a great source of inspiration for medicinal chemists, leading to the emergence of several antineoplastic agents . Among these natural molecular platforms, the steroidal backbone have given rise to the development of potent drugs .…”

“…Cancer is still the world's leading cause of disease-related mortality,a nd pharmacology improvements leading to novel therapeutics remainamajor focus in the medicinal chemistry research community.W ith this mindset, the development of novel anticancer agents from diverse natural compounds has been ag reat source of inspiration for medicinal chemists, leading to the emergenceo fs everala ntineoplastic agents. [1][2][3] Amongt hese natural molecular platforms, the steroidal backbone have given rise to the development of potent drugs. [4][5][6][7] In our continuous effort to develop novel therapeutic agents, we have generatedv arious series of aminosteroid derivatives and reporteds tructure-activity relationship (SAR) studies which highlight their strong cytotoxic properties on cancer cells.…”