Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

Abstract

Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure-activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.

Total Synthesis and Stereochemistry Assignment of Nucleoside Antibiotic A‐94964

“…In fact, a variety of uridine‐derived antibiotics have been evolved in nature to target MraY as effective antimicrobial agents, those include liposidomycins, caprazamycins, mureidomycins, pacidamycins, sansanmycins, muraymycins, capuramycins, and tunicamycins [5, 6] . Chemical synthesis of these complex nucleoside antibiotics and their analogs to elucidate structure–activity relationship and to deliver promising therapeutic candidates has attracted great attention [7–10] …”

“…[5,6] Chemical synthesis of these complex nucleoside antibiotics and their analogs to elucidate structure-activity relationship and to deliver promising therapeutic candidates has attracted great attention. [7][8][9][10] A-94964, identified by Daiichi-Sankyo researchers from the fermentation broth of Streptomyces sp. SANK 60404 in 2008, represents a structurally unique nucleoside antibiotic targeting MraY (IC 50 = 1.1 μg mL À 1 ).…”

Novel Indole-Containing Hybrids Derived from Millepachine: Synthesis, Biological Evaluation and Antitumor Mechanism Study

“…However, the investigation of NPs for drug discovery is hampered by various inevitable difficulties, such as the low amount of NPs available for pharmacological evaluation, the limited availability of natural resources, the difficulty of total chemical synthesis, and the relatively low bioavailability in NPs [ 2 , 3 ]. Therefore, searching for small molecular compounds based on the structures of natural products is an important strategy for drug discovery [ 4 ]. The high structural diversity and various bioactivities of NPs provide diverse scaffolds for NP-based drug discovery.…”

Integrated molecular network and HPLC‐UV‐FLD analysis to explore antioxidant ingredients in camellia nitidissima Chi

“…Molecular Network (MN) is a tandem mass spectrometry (MS) data organization method that has been introduced in the fields of drug discovery, metabolomics, and medicine fields (Quinn et al., 2017). It has a useful application in studying natural products derived from microorganisms, marine organisms, fungi, plants, and others (Allard et al., 2016; Arbour, & Imperiali, 2020; Shen, & Hao, 2020; Zhang et al., 2018). The strategy is based on comparing the theoretical MS/MS spectra with the original MS/MS spectra to establish a relative network.…”