Foreword

Approximately 50% of modern medicines are derived from or inspired by natural products, highlighting the crucial role of natural product chemistry in drug discovery. The isolation, structural determination, and biological activity elucidation of natural compounds are key steps in this process. Advances in isolation and purification techniques, especially chromatography, have been indispensable in finding novel bioactive compounds. For example, HPLC is widely used for isolation and purification. Advanced analytical techniques such as NMR spectroscopy, mass spectrometry (MS), X-ray crystallography, and electronic circular dichroism are essential for precise structural determination. Recent developments in high-resolution LC-MS, molecular networking, and chemometric analysis have greatly enhanced the identification of novel compounds with unique structures and activities. These methods allow effective identification of new bioactive natural products from complex matrices, even with limited sample amounts, improving the speed and accuracy of discovering unknown compounds. Additionally, understanding the biosynthetic pathways of secondary metabolites offers valuable insights into their natural formation processes. This special issue highlights recent advancements in identifying novel natural products, featuring 1 review and 7 original research articles that provide insights into the latest strategies and technologies in bioactive natural product discovery for drug development.

Saito et al. provided an extensive review of spiromeroterpenoids, a class of natural products with a distinctive spiro-ring structure. Meroterpenoids, primarily found in fungi, microorganisms, algae, and plants, are unique terpenoids produced via hybrid biosynthetic pathways. This review focuses on plant-derived meroterpenoids that contain a spiro-ring formed by a terpene and a non-terpene, summarizing their plant sources, structures, biosynthetic pathways, and biological activities. The authors emphasized the structural diversity of these compounds and the ongoing potential for discovering novel natural products as purification and structural analysis techniques improve.

Fukaya et al. conducted a phytochemical study on Paederia scandens (Rubiaceae), resulting in the isolation and structural determination of 3 novel iridoid glycosides, one of which is a sulfur-containing compound. The authors proposed a new biosynthetic pathway for sulfur-containing iridoid glycosides, a type of natural product rarely seen outside Allium species, known for their sulfur-containing compounds. This study provides important insights for exploring sulfur-containing natural compounds with biological activities such as antimicrobial and anticancer properties. Further studies on the anticancer effects of these iridoid glycosides are expected to contribute to drug discovery efforts.

Watanabe et al. performed a phytochemical investigation of Croton argyratus (Euphorbiaceae), isolating 2 new halimane-type diterpenes, crotargyolides A and B, along with a crotofolane-type diterpene and 2 known clerodane diterpenes. This study is the first to investigate the roots of this plant, leading to the isolation of these rare compounds. Crotargyolide A was likely produced from the basic labdane skeleton through a 1,2-hydride shift, oxidation, and lactonization, according to the general biosynthetic pathway to Ahrimanes. Moreover, the isolation of related known clerodane diterpenes, such as junceic acid and epoxyjunceic acid, suggested an alternative biosynthetic pathway starting from junceic acid, involving epoxidation, epoxy ring-opening, 1,2-alkyl rearrangement, and lactonization. This study significantly enhances our understanding of diterpene biosynthesis and the chemical diversity of this plant family.

Yoshizawa et al. reported the isolation and structural determination of 2 new isoflavone glucosides from the underground parts of Iris florentina (Iridaceae). Additionally, the previously isolated isoflavone derivatives from this plant were evaluated for their inhibitory effects on advanced glycation end product formation, with 3 compounds exhibiting inhibitory activity comparable to the positive control, aminoguanidine. This study represents the first isolation of triglucosyl isoflavonoids from an Iridaceae plant and provides further insights into the chemical diversity and bioactive potential of this plant family.

Tateiwa et al. identified a novel retinoid X receptor (RXR) agonist from Boenninghausenia albiflora var. japonica (Rutaceae), isolating 14 coumarins, including a new compound and evaluating their RXRα agonist activity. Among these compounds, daphnoretin methyl ether, a known biscoumarin exhibited strong RXRα agonist activity, highlighting the therapeutic potential of natural RXR agonists as alternatives to synthetic compounds, which often have adverse side effects. This study underscores the significance of RXRα as a target for therapeutic applications in cancer and metabolic disorders, contributing to the development of safer alternatives.

Kikuchi et al. isolated acidic triterpenoid saponins from Silene vulgaris (Caryophyllaceae) using a methylation-based isolation and LC-MS analysis strategy. Through the characteristic MS and MS/MS fragmentations of 5 isolated methylated triterpenoid saponins, a total of 22 acidic triterpenoid saponins, including 18 previously unreported compounds, were identified using LC-MS analysis. This study provided a rapid and effective method for identifying acidic saponins in Silene species, enhancing our understanding of their distribution within this genus. The study also emphasizes the value of LC-MS analysis as a fundamental tool for future chemometric studies, showing that it is an effective method for identifying previously unknown saponins with glucuronic acid in sugar chains, which warrants further data accumulation.

Zhao et al. utilized the Global Natural Product Social Molecular Networking (GNPS) and the Small Molecule Accurate Recognition Technology (SMART) techniques to facilitate the isolation of isopentenyl flavonoids from Daphne giraldii Nitsche, successfully isolating 6 flavonoids, 3 of which were new compounds. The GNPS molecular network technology based on LC-tandem mass spectrometry (LC-MS/MS) and SMART technology, along with NMR, enabled the structure-oriented separation of these compounds, ensuring the efficient and precise separation of the targeted plant metabolites. Furthermore, all compounds were evaluated for their cytotoxic activity against Hep3B cells, with 2 compounds showing significant cytotoxicity. This research exemplifies how modern analytical tools can significantly enhance traditional separation and structural elucidation methods, contributing to more effective natural product discovery.

Kanai et al. used a ¹H-NMR-based biochemometric strategy to identify diarylheptanoid compounds as transient receptor potential vanilloid 1 (TRPV1)-stimulating agents from Alpinia officinarum rhizomes. By combining TRPV1 activity intensity with ¹H-NMR data and employing multivariate analysis, they identified specific spectral bands corresponding to active compounds, enabling the rapid identification of diarylheptanoids as the active compounds. The TRPV1-stimulating activity was further validated at the cellular level. This study highlights the potential of ¹H-NMR spectroscopy for chemometric analysis, offering an efficient method to determine the chemical classes responsible for bioactive properties in complex crude drug extracts while minimizing the number of assays and isolation steps.

This special issue provides a comprehensive overview of recent advancements in natural product chemistry, highlighting the integration of traditional isolation methods with modern analytical and computational techniques. It emphasizes the importance of accurate structural analysis as the first crucial step in natural product discovery. We extend our gratitude to all contributing authors for their valuable insights and contributions to this field.