Malignant melanoma is an aggressive cancer requiring new therapeutic options. Isodonal, a known spirolactone type ent-kauranoid, was obtained in high abundance from Isodon oresbius. Phenotypic screening of isodonal revealed its antiproliferative activity against A375 melanoma cells. In the structural modification to prompt its selection for optimization, we synthesized a focused library of thirty new ester derivatives (8-37) at C-6 position of isodonal. All analogues exhibited enhanced potency (IC50 = 0.73-4.43 μM) over isodonal, with the C-6 4-fluorocinnamate ester 29 being most potent (IC50 = 0.73 μM; ∼10-fold improvement). Structure-activity relationship analysis revealed that conjugated systems (e.g., cinnamoyl) boost activity, and that specific substitutions in benzoate derivatives can modulate selectivity between melanoma and normal cells. Compound 29 was found to suppress proliferation, induce apoptosis and G2/M phase arrest, and elevate ROS levels in A375 cells. This study delivers a potent lead compound and a framework for the natural product-inspired development of anti-melanoma therapeutics.

A new pyrone derivative, spiropestalopyrone (1), along with four known analogs, pestalopyrones A–D (2–5), was isolated from the endophytic fungus Pestalotiopsis sp. HS5 (Sporocadaceae) inhabiting the leaves of Isodon xerophilus (C. Y. Wu H. W. Li) H. Hara (Lamiaceae). Structural elucidation of 1 through comprehensive spectroscopic analyses (1D and 2D NMR, HR-ESI-MS, IR) revealed a unique spiroketal-containing architecture. The absolute configuration was determined through analysis of ROESY spectrum, DFT-GIAO chemical shift calculations coupled with DP4+ probability analysis, and TDDFT ECD calculations. Notably, compound 1 exhibited moderate inhibitory activity against LPS-induced NO production in RAW264.7 macrophages (24.14

Current analgesics suffer from efficacy and safety limitations, driving demand for novel low-voltage-gated calcium channel (LVGCC) modulators, particularly Cav3.2, an essential target in modern analgesic drug development. We develop a mild, one-step ring contraction of α-chlorocyclobutanones to efficiently afford highly substituted cyclopropyl ketones. Mechanistic studies demonstrate that the ring-contraction process features a concerted quasi-Favorskii rearrangement. Leveraging this approach, three pseudo-meroditerpenoids (41b, 42, and 43) bearing an unprecedented 6/6/3 scaffold are identified as novel Cav3.2 modulators. Compound 41b (20 mg/kg) is a potent Cav3.2 inhibitor and exhibits antinociceptive effects comparable to those of Z944 (10 mg/kg), an LVGCC inhibitor currently under clinical investigation, in two mouse pain models. Compounds 42 and 43 preferentially retard the inactivation kinetics of Cav3.2 without inhibiting its peak current.

Three new triterpenoids, henridilactones P-R (1-3) and two new dibenzocyclooctadiene lignans, henrilignans A and B (11 and 12), alongside twelve known analogues (4-10 and 13-17) were isolated from the stems and leaves of Schisandra henryi subsp. yunnanensis. The structures and absolute configurations of new compounds were elucidated by comprehensive 1D and 2D NMR, HRESIMS, electronic circular dichroism analyses, and theoretical calculations. In bioactivity evaluation, the isolated triterpenoids (1-10) exhibited moderate neurite outgrowth in differentiated PC12 cells at 10 µM (differentiation rates 10.09%-12.96%; positive control 50 ng/mL NGF, 19.71%). Furthermore, henridilactone P (1) exhibited a binding affinity with an equilibrium dissociation constant (KD) of 3.286 × 10- 4 M (reference compound PF-06446846, KD = 8.008 × 10- 5 M).

Aurantiacin A (1), a unique ascorbylated meroditerpenoid composed of an unusual 9-epi-spiro-lactone-type ent-kaurane diterpenoid core, ascorbic acid (vitamin C), and syringic acid, and three new 9-epi-spiro-lactone-type ent-kauranoids, aurantiacins B-D (2-4), were isolated from an untapped species, Isodon aurantiacus. Their structures were determined by spectroscopic data analysis, semisynthesis, floating chirality distance geometry calculations, and quantum chemical calculations. Aurantiacin A (1) was found to induce lysosomal biogenesis, and the potential mechanisms underlying this effect were preliminarily explored.

Eight new diterpenoids, leucophyllusins A-H (1-8), along with 19 known analogues (9-27) were obtained from the aerial parts of Isodon leucophyllus. Among them, abietanoids represented the predominant structural class. The structures and absolute configurations of all new compounds were unambiguously determined through a comprehensive analytical approach combining 1D/2D NMR, HRESIMS, and quantum chemical calculations. All compounds were tested for their inhibitory activity against arachidonic acid-induced platelet aggregation and lipopolysaccharide-stimulated nitric oxide production in RAW264.7 macrophage cells. However, none exhibited significant activity relative to the positive controls.

Glutinosasins A-D (1-4), four novel 8,14-seco-ent-kaurane diterpenoids featuring a beta-carbonyl enol moiety, along with glutinosasin E (5), a new ent-kaurane diterpenoid, were isolated from the aerial parts of Isodon glutinosus. Their structures were elucidated through a combinatorial use of spectroscopic methods and single-crystal X-ray diffraction. Quantum chemical calculations further validated the unique structures of 1-4 and supported the presence of enol-enol tautomerism within these molecules. Notably, 4 demonstrated selective inhibitory activity against SW480 tumor cells, with an IC50 value of 2.33 mu M, and induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner.

Natural products (NPs) are invaluable resources for drug discovery, characterized by their intricate scaffolds and diverse bioactivities. AI drug discovery & design (AIDD) has emerged as a transformative approach for the rational structural modification of NPs. This review examines a variety of molecular generation models since 2020, focusing on their potential applications in two primary scenarios of NPs structure modification: modifications when the target is identified and when it remains unidentified. Most of the molecular generative models discussed herein are open-source, and their applicability across different domains and technical feasibility have been evaluated. This evaluation was accomplished by integrating a limited number of research cases and successful practices observed in the molecular optimization of synthetic compounds. Furthermore, the challenges and prospects of employing molecular generation modeling for the structural modification of NPs are discussed.

Ergopolyketides A–D, presumably biosynthesized through Diels-Alder additions between ergosterol and polyketides, along with two new andrastin-type meroterpenoids, isopenicins D and E, were isolated from the co-culture of endophytic fungi Penicillium sp. sh18 and Pestalotiopsis sp. HS30, respectively, inhabiting Isodon species. The structures of these compounds were elucidated using spectroscopic analysis, single crystal X-ray diffraction, and quantum chemical calculations. Isopenicin D and a known compound, peniandrastin D exhibited moderate cytotoxic activities against human cancer cell lines HL-60, A549, and SMMC-7721, with IC50 values ranging from 13.37 to 29.17 μM.

Isoxerophilusins A (1) and B (2), two unprecedented diterpene heterodimers biogenetically from ent-atisanes and abietanes, were isolated from the rhizomes of Isodon xerophilus. Their structures were determined by extensive spectroscopic analysis and single-crystal X-ray diffraction. Selective esterification of 1 generated 11 new derivatives. All derivatives showed excellent α-glucosidase inhibitory activity in comparison to acarbose. Compounds 12 and 13 demonstrated significant inhibition against α-glucosidase with IC50 values of 4.92 and 3.83 μM, respectively.

Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.

The [4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration.

Scoparodane C (1), a diterpenoid with a rare 3,4-seco-3-nor-2,11-epoxy-ent-clerodane scaffold, was obtained from the aerial parts of Isodon scoparius, along with isocopariusines A-E (2-6), five ent-clerodanoids featuring a 5/6-fused ring system, and isocopariusines F-H (7-9), three common ent-clerodanoids. The structures of these previously undescribed compounds were established by a combination of spectroscopic analysis, X-ray diffraction, chemical derivatization, and quantum chemical calculation. Remarkably, isocopariusine B (3) showed strong resistance reversal activity against fluconazole-resistant Candida albicans.

AbstractThree new ent-kaurane diterpenoids, silvaticusins A–C (1–3), along with a new ent-kaurane dimer silvaticusin D (4) were isolated from the aerial parts of Isodon silvaticus. The structures of these new compounds were established mainly by comprehensive analysis of their NMR and MS data. The absolute configuration of compounds 1 and 4 were determined using a single-crystal X-ray diffraction and computational methods, respectively. Compounds 2 and 3 were found to exhibit remarkable cytotoxic effects against five human tumor cell lines (HL-60, A-549, SMMC-7721, MDA-MB-231, and SW-480), with IC50 values spanning from 1.27 ± 0.08 to 7.52 ± 0.33 μM. Graphical Abstract

Four new 14(13 → 12)-abeolanostane triterpenoids featuring extended π -conjugated systems, kadcoccitanes E–H ( 1 – 4 ), were obtained from the stems of Kadsura coccinea through using a HPLC − UV-guided approach. Their structural and configurational determination was accomplished through extensive spectroscopic analysis coupled with quantum chemical calculations. Kadcoccitanes E–H were tested for their cytotoxic activities against five human tumor cell lines (HL-60, A-549, SMMC-7721, MDA-MB-231, SW-480) but none of them exhibited activities at the concentration 40 μM. Graphical Abstract

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

(+)-Isoscopariusins B (1) and C (2), two meroditerpenoids containing a 6/6/4 tricyclic carbon skeleton and seven continuous stereocenters, were identified from Isodon scoparius. The structures were determined by nuclear magnetic resonance analysis and concise biomimetic syntheses from readily available alkene 5 in seven and six steps, respectively. An intermolecular [2+2] photocycloaddition with cooperative catalysis of a Lewis acid and an Ir photocatalyst was used to construct a cyclobutane core with four stereogenic centers.

Abstract Ferroptosis is an iron-dependent cell death induced by the oxidation of polyunsaturated fatty acids. In recent years, ferroptosis has garnered tremendous potential in cancer therapy. However, the significance pathways of ferroptosis in chronic myeloid leukemia (CML) therapy are still poorly understood. Here, we investigated the role of a critical antioxidant protein, thioredoxin 1 (Trx1), in regulating ferroptosis in CML cells. First, we showed that Trx1 expression was higher in patients with CML than in healthy controls. Specifically, Trx1 knockdown suppressed cell growth and slowed tumor progression in xenograft models. Pharmacological inhibitors of Trx1 also attenuated cell growth, reduced colony formation, and caused CML cell death. Second, we showed that decreased Trx1 expression enhanced the cytotoxicity of the glutathione (GSH) biosynthesis inhibitor buthionine sulfoximine. Mechanistically, the combined inhibition of Trx1 and GSH synthesis disrupted the homeostasis of cellular reactive oxygen species as evidenced by increased ROS and malondialdehyde; and decreased GSH. Importantly, inhibition of Trx1 significantly resentisized GSH-depletion induced ferroptosis in CML cells. Finally, targeting Trx1 and GSH synthesis with small-molecule inhibitors caused a synergic effect on CML cells both in vitro and in vivo.Together, these results highlight an critical role of Trx1 in GSH-depletion induced ferroptosis and provide clues for dual inhibition of the Trx1 and GSH system as a combinatorial strategy for CML therapy.

Twenty new ent-kaurane diterpenoids, wardiisins A-T (1-20), along with two previously undescribed artefactual compounds (21 and 22) and twelve known analogues (23-34), were isolated from the aerial part of Isodon wardii. Their structures were elucidated by comprehensive analysis of spectroscopic data and single-crystal X-ray diffraction, and most of them were found to bear unusual C-12 oxygenation. Compounds 4, 7, 8, 19, 20, 21 exhibited remarkable cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MDA-MB-231, and SW480, with IC50 values ranging from 0.3 to 5.2 μM. Moreover, 7 was found to induce G2/M cell cycle arrest and promote apoptosis in SW480 cell lines.

Abstract Structure elucidation of novel compounds with high flexibility and trace amount is among the hardest tasks in natural product research. In the present study, trace metabolites-targeted LSC strategy was applied for Penicillium sp. sh18 to provide two types of novel scaffolds, heterotetrameric FcA, pentetrafuranone A (1) and heterotrimeric FcA, pentrifuranones A and B (2 and 3). The flexibility and sample shortage obstruct the accessibility to crystallographic and chemical modification methods to determine their structures. Furthermore, the complexity of the structure and the presence of an uncommon "conditional chiral center", coupled with the permutation of NMR data, made conventional techniques ineffective. To overcome these challenges, a combinational method with extensive NMR analysis, including pure-shift 1H NMR, LR-HSQMBC, and multi-step conformational sampling method coupled with spatial sensitive parameters RDC and QID, and fc-rDG/DDD approaches was employed to establish the planar structures and cross-validate their configurations. In addition, antimalaria activity was evaluated and 2 exhibits significant inhibitory effect against Plasmodium falciparum 3D7 at asexual blood-stage with IC50 of 0.72 µM. The present study offers new scaffolds that exhibit significant antimalaria activity. Moreover, it showcases how spatially sensitive-based analytical strategies can serve as a crystallography-independent approach for assigning structure and configuration of intricate natural products.