Approaches to Configuration Determinations of Flexible Marine Natural Products: Advances and Prospects

Abstract

Flexible marine natural products (MNPs), such as eribulin and bryostatin, play an important role in the development of modern marine drugs. However, due to the multiple chiral centers and geometrical uncertainty of flexible systems, configuration determinations of flexible MNPs face great challenges, which, in turn, have led to obstacles in druggability research. To resolve this issue, the comprehensive use of multiple methods is necessary. Additionally, configuration assignment methods, such as X-ray single-crystal diffraction (crystalline derivatives, crystallization chaperones, and crystalline sponges), NMR-based methods (JBCA and Mosher’s method), circular dichroism-based methods (ECCD and ICD), quantum computational chemistry-based methods (NMR calculations, ECD calculations, and VCD calculations), and chemical transformation-based methods should be summarized. This paper reviews the basic principles, characteristics, and applicability of the methods mentioned above as well as application examples to broaden the research and applications of these methods and to provide a reference for the configuration determinations of flexible MNPs.

New Antibacterial Diterpenoids from the South China Sea Soft Coral Klyxum molle

“…Normal Phase-High Performance Liquid Chromatography (NP-HPLC) CHIRALPAK ® IC (250 mm × 4.6 mm, 5 µm, Daicel Corporation, Osaka, Japan) (n-hexane/isopropanol (99.7:0.3), 1.0 mL/min) ( 2 : t R = 4.6 min; 3 : t R = 5.5 min) was used to successfully separate the mixture into 2 and 3 . The absolute configurations (ACs) of 2 and 3 were further established by TDDFT-ECD calculations, a reliable approach to determine the ACs of natural products with chiral carbons near the chromophore groups [ 23 , 24 , 25 , 26 ]. As shown in Figure 3 , the Boltzmann-averaged ECD spectrum of (1 R ,2 R ,4 S ,13 R ,15 E )- 2 matched to the experimental ECD spectrum of 2 , and the Boltzmann-averaged ECD spectrum of (1 R ,2 R ,4 S ,13 S ,15 E )- 3 matched to the experimental ECD spectrum of 3 .…”

New Antibacterial Diterpenoids from the South China Sea Soft Coral <i>Klyxum molle</i>

“…Normal Phase-High Performance Liquid Chromatography (NP-HPLC) CHIRALPAK ® IC (250 mm × 4.6 mm, 5 µm, Daicel Corporation, Osaka, Japan) (n-hexane/isopropanol (99.7:0.3), 1.0 mL/min) (2: t R = 4.6 min; 3: t R = 5.5 min) was used to successfully separate the mixture into 2 and 3. The absolute configurations (ACs) of 2 and 3 were further established by TDDFT-ECD calculations, a reliable approach to determine the ACs of natural products with chiral carbons near the chromophore groups [23][24][25][26]. As shown in Figure 3, the Boltzmann-averaged ECD spectrum of (1R,2R,4S,13R,15E)-2 matched to the experimental ECD spectrum of 2, and the Boltzmann-averaged ECD spectrum of (1R,2R,4S,13S,15E)-3 matched to the experimental ECD spectrum of 3.…”

Advanced Methods for Natural Products Discovery: Bioactivity Screening, Dereplication, Metabolomics Profiling, Genomic Sequencing, Databases and Informatic Tools, and Structure Elucidation

“…In the pharmaceutical industry, having pure NP or MNP with their 3D structure elucidated is mandatory, as impurities and/or different stereoisomers can have totally adverse effects on human health, such as in the case of Thalidomide ® . Numerous strategies have been developed to overcome limitations, including the scarce amount of sample availability, the presence of stereogenic centers, multiple chiral quaternary atoms, or the chirality of flexible systems [ 290 , 291 ]. Depending on the specific physical and chemical characteristics of NP, their stereochemical features can be studied by X-ray diffraction, chiroptical methods, chemical derivatization, NMR-based methods, computational NMR methods, and genomics ( Figure 6 ).…”