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

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.

MS/MS-Based Molecular Networking: An Efficient Approach for Natural Products Dereplication.

Natural products (NPs) have historically played a primary role in the discovery of small-molecule drugs. However, due to the advent of other methodologies and the drawbacks of NPs, the pharmaceutical industry has largely declined in interest regarding the screening of new drugs from NPs since 2000. There are many technical bottlenecks to quickly obtaining new bioactive NPs on a large scale, which has made NP-based drug discovery very time-consuming, and the first thorny problem faced by researchers is how to dereplicate NPs from crude extracts. Remarkably, with the rapid development of omics, analytical instrumentation, and artificial intelligence technology, in 2012, an efficient approach, known as tandem mass spectrometry (MS/MS)-based molecular networking (MN) analysis, was developed to avoid the rediscovery of known compounds from the complex natural mixtures. Then, in the past decade, based on the classical MN (CLMN), feature-based MN (FBMN), ion identity MN (IIMN), building blocks-based molecular network (BBMN), substructure-based MN (MS2LDA), and bioactivity-based MN (BMN) methods have been presented. In this paper, we review the basic principles, general workflow, and application examples of the methods mentioned above, to further the research and applications of these methods.

Voacafrines A-N, aspidosperma-type monoterpenoid indole alkaloids from Voacanga africana with AChE inhibitory activity.

Fourteen undescribed monoterpenoid indole alkaloids, voacafrines A-N, along with 7 known monoterpenoid indole alkaloids were isolated from the seeds of Voacanga africana Stapf. Among them, voacafrines A-G were aspidosperma-aspidosperma type bisindole alkaloids, while voacafrines H-N were aspidosperma-type monomers. Their structures and absolute configurations were elucidated by a combination of NMR, MS, and ECD analyses. Voacafrines A-C were characterized by an acetonyl moiety at C-5', while voacafrine H possessed a methoxymethyl moiety at C-14 within aspidosperma-type alkaloids. The acetylcholinesterase (AChE) inhibitory activity and cytotoxicity of voacafrines A-N were evaluated. Voacafrines A-C and E-G were bisindole alkaloids that exhibited AChE inhibitory activity with IC50 values of 4.97-33.28 µM, while voacafrines I and J were monomers that showed cytotoxicity against several human cancer cell lines with IC50 values of 4.45-7.49 µM.

Bousmekines A-E, New Alkaloids from Two Bousigonia Species: B.angustifolia and B. mekongensis.

Four new monoterpenoid indole alkaloids, bousmekines A-D (1-4), and one new pyranopyridine alkaloid, bousmekine E (5), were isolated from the twigs and leaves of Bousigonia angustifolia and Bousigonia mekongensis. Their structures including absolute configurations were elucidated by a combination of MS, NMR, ECD calculation, and single-crystal X-ray diffraction analysis. Compound 2 was an eburnea-type MIAs characterized by a rare chlorine atom while 5 possessed a novel pyranopyridine moiety. Their cytotoxicities against several human cancer cell lines were evaluated and compound 1 exhibited significant cytotoxicity with IC50 values of 0.8-7.4 µM.

Bousangine A, a novel C-17-nor aspidosperma-type monoterpenoid indole alkaloid from Bousigonia angustifolia.

Two new monoterpenoid indole alkaloids, bousangines A (1) and B (2), were isolated from the twigs and leaves of Bousigonia angustifolia. Their structures including absolute configurations were elucidated by a combination of MS, NMR, ECD calculation, and single-crystal X-ray diffraction analysis. Bousangine A (1) possessed a rearrangement pentacyclic skeleton derived from aspidosperma-type alkaloids with C-17 degradation. Their antiproliferative activity against several human cancer cell lines were evaluated.

Melotenuines A-E, cytotoxic monoterpenoid indole alkaloids from Melodinus tenuicaudatus.

Five new monoterpenoid indole alkaloids, melotenuines A-E (1-5), along with 18 known indole alkaloids, were isolated from the twigs and leaves of Melodinus tenuicaudatus. The structures of the new alkaloids were determined by a combination of MS, NMR and ECD analysis. Melotenuine A (1) represents the first example of aspidosperma-meloscandonine type bisindole alkaloids characterized by a methylene bridge between the two monomers, while melotenuine B (2) possessed a rare eburnamine-melsocandonine skeleton. All of the new indole alkaloids were evaluated for in vitro cytotoxicities against five human cancer cell lines. Among them, alkaloid 4 showed specific cytotoxicity against HL-60 cell line with IC50 value (5.15 ±â€¯0.16 µM) comparable with that of positive control.