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Previously, we reported that azamollugin, an aza-derivative of mollugin, exhibited potent inhibitory activity on NO production in LPS-stimulated RAW 264.7 cells. Further investigations in this study revealed that azamollugin not only suppressed iNOS gene expression regulated by NF-κB, but also inhibited LPS-induced IFN-β expression, which is known to be regulated by IRF3. Azamollugin exhibited an inhibitory activity on LPS-induced IRAK1 activation, suggesting inhibitory effect on the MyD88-dependent pathway. Furthermore, azamollugin inhibited LPS-induced phosphorylation of IRF3 and its upstream factor, TBK1/IKKε, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR4. In addition, azamollugin also suppressed poly(I:C)-induced phosphorylation of TBK1 and IRF3, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR3. These results suggest that azamollugin has inhibitory activity against both the MyD88-dependent and TRIF-dependent pathways, respectively., Competing Interests: Declarations. Conflict of interest: The authors declare no competing financial interests., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Oxomollugin is a degraded product of mollugin and was found to be an active compound that inhibits LPS-induced NF-κB activation. In this study, we investigated the inhibitory activity of oxomollugin, focusing on TLR4 signaling pathway, resulting in NF-κB activation. Oxomollugin inhibited the LPS-induced association of essential factors for initial activation of TLR4 signaling, MyD88, IRAK4 and TRAF6. Furthermore, oxomollugin showed suppressive effects on LPS-induced modification of IRAK1, IRAK2 and TRAF6, LPS-induced association of TRAF6-TAK1/TAB2, and followed by IKKα/β phosphorylation, which critical in signal transduction leading to LPS-induced NF-κB activation. The consistent results suggested that oxomollugin inhibits LPS-induced NF-κB activation via the suppression against signal transduction in TLR4 signaling pathway.The activities of oxomollugin reported in this study provides a deeper understanding on biological activity of mollugin derivatives as anti-inflammatory compounds., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Ceramicines are a series of limonoids which were isolated from the barks of Malaysian Chisocheton ceramicus (Meliaceae), and were known to show various biological activity. Six new limonoids, ceramicines U-Z (1-6), with a cyclopentanone[α]phenanthrene ring system with a β-furyl ring at C-17 were isolated from the barks of C. ceramicus. Their structures were determined on the basis of the 1D and 2D NMR analyses, and their absolute configurations were investigated by CD spectroscopy. Ceramicine W (3) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 1.2 µM. In addition, the structure-antimalarial activity relationship (SAR) of the ceramicines was investigated to identify substituent patterns that may enhance activity. It appears that ring B and the functional groups in the vicinity of rings B and C are critical for the antimalarial activity of the ceramicines. In particular, bulky ester substituents with equatorial orientation at C-7 and C-12 greatly increase the antimalarial activity., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Ceramicines are a series of limonoids that were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and were known to show various biological activity. Four new limonoids, ceramicines Q-T (1-4) were isolated from the barks of C. ceramicus, and their structures were determined on the basis of the 1D and 2D NMR analyses in combination with calculated 13 C chemical shift data. Ceramicines Q-T (1-4) were established to be new limonoids with a cyclopentanone[α]phenanthren ring system with a β-furyl ring at C-17, and without a tetrahydrofuran ring like ceramicine B, which is characteristic of known ceramicines. Ceramicine R (2) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 2.8 µM., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Bioactivity guided separation of Chukrasia velutina root methanolic extract led to the isolation of nine new isopimarane diterpenoids, chukranoids A-I (1-9). The absolute configuration was then assigned by comparing the experimental CD spectra and the calculated CD spectra. Chukranoids A-I (1-9) showed moderate antimalarial activity against Plasmodium falciparum 3D7 strain. It seems that conjugate system in the isopimarane skeleton may influence their antimalarial activity., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Bioactivity-guided separation of the methanol extract of Calophyllum scriblitifolium bark led to the isolation of five new pyranocoumarins, caloforines A-E (1-5) and two new coumarins, caloforines F and G (6 and 7). Their structures were elucidated by 1D and 2D NMR spectroscopy, and their absolute configurations were investigated by a combination of CD spectroscopy and DFT calculation. Caloforines A-F (1-6) showed moderate antimalarial activity against Plasmodium falciparum 3D7 strain., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Eight new limonoids, walsogynes H-O (1-8) were isolated from the barks of Walsura chrysogyne, and their structures were determined on the basis of the 1D and 2D NMR data. Walsogynes H-M (1-6) and O (8) were concluded to be 11,12-seco limonoids with a dodecahydro-1H-naphtho[1,8-bc:3,4-c']difuran skeleton, and walsogyne N (7) to be 11,12-seco limonoid sharing a unique dodecahydronaphtho[1,8-bc:5,4-b'c']difuran skeleton. Walsogynes H-O (1-8) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 2.5, 2.6, 1.6, 2.5, 1.5, 2.6, 2.1, and 1.1 µM, respectively., (© 2021. The Japanese Society of Pharmacognosy.)

Two new bisindole alkaloids, bisnaecarpamines A (1) and B (2), possessing a vobasine-sarpagine type skeleton were isolated from the bark of Tabernaemontana macrocarpa Jack. Their structures were elucidated by extensive spectroscopic methods and chemical correlation. The absolute configurations of compounds 1 and 2 were established using TDDFT-ECD calculation of the selected isomers. Bisnaecarpamine A exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 28.8 µM.

Two new bisindole alkaloids, 12'-O-demethyl-vobtusine-5-lactam and isovobtusine-N-oxide (1 and 2), were isolated from the leaves of Voacanga grandifolia, together with two known bisindole alkaloids. Their structures were elucidated on the basis of 1D and 2D NMR data. 1 and 2 showed potent antimalarial activity against Plasmodium falciparum 3D7 and very low cytotoxic activity against a human cell line, HepG2 cells.

Bioactivity guided separation of Walsura trichostemon stem methanolic extract led to the isolation of four new dammarane (1-4) and two new apotirucallane triterpenoids (5-6), together with one limonoid (7), 11,25-dideacetyltrichostemonate, 12β, 20S, 24R-trihydroxydammar-25-en-3-one and 12β, 20S, 25-trihydroxydammar-23-en-3-one. Compounds 1-7 showed in vitro inhibitory activity on the proliferation of A549, human lung adenocarcinoma cell line.

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 μM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.

The article Cycloartane triterpenoid (23R, 24E)-23-acetoxymangiferonic acid inhibited proliferation and migration in B16-F10 melanoma via MITF downregulation caused by inhibition of both β-catenin.

Two new sarpagine-type indole alkaloids (1 and 2), together with five known alkaloids; 12-methoxy-4-methylvoachalotine (3), 16-demethoxycarbonylvoacamine (4), isositsirikine (5), affinisine (6), affinine (7), were isolated from the bark of Tabernaemontana macrocarpa Jack. The structures of these alkaloids were determined based on spectroscopic data, chemical correlation, and comparison with the literature. 16-Demethoxycarbonylvoacamine (4) showed antiplasmodial activities against Plasmodium falciparum 3D7 and cytotoxic activities against human cell line, HepG2 cells.

Computer hardware development coupled with the development of quantum chemistry, new computational models and algorithms, and user-friendly interfaces have lowered the barriers to the use of computation in the discovery and structure elucidation of natural products. Consequently, the use of computational chemistry software as a tool to discover and determine the structure of natural products has become more common in recent years. In this review, we provide several examples of recent studies that used computer technology to facilitate the discovery and structure determination of various natural products.

Picrasma javanica Blume (Simaroubaceae) is a medium-sized tree that is distributed widely in tropical Asia. In our previous study, we isolated quassinoids from P. javanica bark collected in Myanmar, and reported their antiproliferative activities. In our ongoing research for the discovery of bioactive compounds from Myanmar medicinal plants, two new quassinoids, (16R)-methoxyjavanicin B (1) and (16S)-methoxyjavanicin B (2), along with seven known compounds (3-9), were isolated during the phytochemical investigation of the CHCl 3 soluble portion of the MeOH extract of P. javanica wood. The structures of the new compounds were elucidated by analyses of their spectroscopic data (1D- and 2D-NMR, HRESIMS, and CD). A cytotoxicity assay revealed that compound 8 showed moderate activities against all tested cancer cell lines, the human lung (A549), breast (MCF7), and cervical (HeLa), and the normal fibroblast cell line, with IC 50 values ranging from 48.6 to 65.9 μM. Furthermore, the antibacterial assay demonstrated that 1 and 2 had the highest activities (MIC value of 1.6 μM each), followed by 5 and 3 (MIC values of 3.1 and 6.3 μM, respectively) against the Gram-positive bacterium B. subtilis.

Previously, we reported that cyclolinopeptides (CLs) extracted from flaxseed inhibited receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis from mouse bone marrow cells in vitro. However, mode of action involved in CLs-inhibited osteoclastogenesis has been yet unknown. Therefore, in this study, we investigated the details of inhibitory activity of cyclolinopeptide-F (CL-F) in osteoclastogenesis, as a representative of CLs. CL-F dose-dependently inhibited RANKL-induced osteoclastogenesis (IC 50 0.58 µM) without cytotoxic effects. The inhibition by CL-F was mainly observed in macrophage colony-stimulating factor (M-CSF)-induced proliferation/differentiation phase from M-CSF responsive immature myeloid cells to monocyte/macrophage (M/Mϕ) lineage. Additionally, CL-F also slightly inhibited RANKL-induced differentiation phase from M/Mϕ to mature osteoclasts. Expression of RANKL receptor, RANK, in M-CSF-induced M/Mϕ, i.e. osteoclast progenitor cells, was decreased by CL-F treatment. Furthermore, RT-PCR analysis revealed that CL-F inhibited c-fos gene expression, which is reported to be crucial for RANK expression in osteoclast progenitor cells induced with M-CSF from myeloid lineage cells. These results suggested that CL-F inhibits osteoclastogenesis via down regulation of c-fos expression, which leads to the down-regulation of RANK expression in M-CSF-induced osteoclast progenitors.

Two new bisindole alkaloids, leucophyllinines A (1) and B (2) consisting of eburnane and quebrachamine-type skeletons were isolated from the bark of Leuconotis eugeniifolia, and their structures were elucidated on the basis of spectroscopic data. Leucophyllinines A and B showed antiplasmodial activities against Plasmodium falciparum 3D7.

Taberniacins A (1) and B (2), new indole alkaloids, were isolated from the stems of Tabernaemontana divaricata (Apocynaceae). Structure elucidation of 1 and 2 was based on spectroscopic methods and total synthesis. Each alkaloid showed vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.

We recently reported that (23R, 24E)-23-acetoxymangiferonic acid (23R-AMA), a cycloartane triterpenoid isolated by activity-guided separation from a methanol extract of Garcinia sp. bark, inhibited melanin production via inhibition of tyrosinase (TYR) expression in the B16-F10 melanoma cell line. Since 23R-AMA also inhibited microphthalmia-associated transcription factor (MITF) expression, an upstream factor of TYR, these features of 23R-AMA were thought to be appropriate for development of whitening cosmetics. However, 23R-AMA exhibited growth inhibition other than inhibition of melanin production in B16-F10 cells. Therefore, we investigated biological activities of 23R-AMA in detail, focused on its application as an anti-melanoma compound. In this study, we demonstrated that 23R-AMA inhibited cell proliferation and basic FGF (bFGF)-induced migration in B16-F10 cells. Furthermore, 23R-AMA promoted ser45/thr41 phosphorylation of β-catenin and suppressed its intranuclear accumulation, which was suggested to be related to inhibition of MITF expression. The transcriptional activity of MITF is known to be regulated by phosphorylation via activated ERK. Further investigation revealed that 23R-AMA inhibited phosphorylation of c-Raf, MEK-1, and ERK, and also that of upstream molecules including FAK and c-Src. These results suggested that 23R-AMA inhibited growth and migration of B16-F10 melanoma by regulating both MITF expression and its activity. The activities of 23R-AMA reported in this study are new aspects of cycloartane triterpenoids.

Bioactivity guided separation of Reinwardtiodendron cinereum barks methanol extract led to the isolation of two new onocerane triterpenoids, reinereins A and B (1 and 2), together with three known onocerane triterpenoids. Their structures were elucidated on the basis of NMR spectroscopic data. In vitro cytotoxic activities of the isolated compounds against several type of cancer cells were evaluated.

Ceramicines are a series of limonoids which were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and show various biological activities. Ceramicine B, in particular, has been reported to show a strong lipid droplet accumulation (LDA) inhibitory activity on a mouse pre-adipocyte cell line (MC3T3-G2/PA6). With the purpose of discovering compounds with stronger activity than ceramicine B, we further investigated the constituents of C. ceramicus. As a result, from the bark of C. ceramicus four new ceramicines (ceramicines M-P, 1-4) were isolated, and their structures were determined on the basis of NMR and mass spectroscopic analyses in combination with NMR chemical shift calculations. LDA inhibitory activity of 1-4 was evaluated. Compounds 1-3 showed LDA inhibitory activity, and 3 showed better selectivity than ceramicine B while showing activity at the same order of magnitude as ceramicine B. Since 3, which possess a carbonyl group at C-7, showed better selectivity than 5, which possess a 7α-OH group, while showing activity at the same order of magnitude as 5, we also investigated the effect of the substituent at C-7 by synthesizing several derivatives and evaluating their LDA inhibitory activity. Accordingly, we confirmed the importance of the presence of a 7α-OH group to the LDA inhibitory activity.

The ceramicines, a series of limonoids from Chisocheton ceramicus (Meliaceae), were evaluated for anti-melanin deposition activity on α-melanocyte stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-treated B16-F10 melanoma cell, and several ceramicines were found to be active. The structure-activity relationship of ceramicines as anti-melanin deposition inhibitors was deduced. Furthermore, the mechanism of anti-melanin deposition activity of ceramicine B, a major constituent of C. ceramicus that showed potent anti-melanin deposition activity, was investigated. Tyrosinase enzymatic activity and tyrosinase mRNA expression were not affected by ceramicine B. The anti-melanin deposition activity of ceramicine B was shown to be related to the downregulation of tyrosinase protein expression. These results suggest that ceramicines have potential to be used as depigmentation agents.

Mollugin, a naphthoquinone derivative, was reported to possess various biological activities such as anti-inflammatory and anti-tumor activity. Mollugin isolated from Rubia tinctorum roots inhibited lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 macrophages. However, mollugin synthesized for further investigation of its anti-inflammatory mechanism showed weak activity in addition to unstable assay results. From the result of analysis on a degradation product of mollugin, oxomollugin was found to be the main active substance of mollugin degradation, showing a potent inhibitory activity on NO-production including nuclear factor kappa B signals.

Two new aromadendrane sesquiterpenoids, dysosesquiflorins A and B (1 and 2), were isolated from Dysoxylum densiflorum bark, and their structures were elucidated on the basis of NMR spectroscopic data. These dysosesquiflorins showed in vitro cytotoxic activity against several cancer cell lines.

Three new terpenoids, opaciniols A-C (1-3), were isolated from the barks of Garcinia opaca, together with malabarica-17,21-dien-3β,14-diol (4) and 13βH-malabarica-14,17,21-trien-3β-ol (5). Their structures were determined on the basis of NMR spectroscopic data. 3 and 4 showed moderate cytotoxicity against HL-60 cells.

Determination of the absolute configuration (AC) is often a challenging aspect in the structure elucidation of natural products. When chiral compounds possess appropriate chromophore(s), electronic circular dichroism (ECD) may provide a powerful approach to the determination of their absolute configuration. Recently, ECD calculations by time-dependent density functional theory (TDDFT) have come to be used more commonly. In the present review, we give several examples of recent studies using TDDFT-calculated ECD spectra for the AC determination of natural products.

Five new diterpenoids belonging to labdane and isopimarane skeletons, mumic acids A-E (1-5), have been isolated from mumiyo. Their structures and absolute configurations were elucidated on the basis of spectroscopic data and chemical derivatization.

Two new limonoids, sanjecumins A (1) and B (2), have been isolated from the leaves of Sandoricum koetjape, together with sandoripins A (3) and B (4). Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Sandoripins A (3) and B (4) moderately inhibited nitric oxide production in mouse macrophage-like cell line J774.1 stimulated by lipopolysaccharide.

Two new isocoumarin glucosides, haworforbins A (1) and B (2), and a new chromone, haworforbin C (3), have been isolated from Haworthia cymbiformis. Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Haworforbin C (3) exhibited moderate inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cell line.

Three new limonoids, ceramicines J (1), K (2), and L (3), were isolated from the hexane layer of Chisocheton ceramicus bark extract. Their structures were elucidated from 1D and 2D NMR data. Ceramicines J-L (1-3) exhibited dose-dependent moderate cytotoxicity against the HL-60 cell line.

A new indole alkaloid, leucoridine A N-oxide (1), consisting of two units of a strychnan type of skeleton, was isolated from the leaves of Leuconotis griffithii. Its structure was elucidated by various spectroscopic means such as NMR and MS, and also by chemical means. Antiplasmodial activity against Plasmodium falciparum 3D7 of indole alkaloids isolated from L. griffithii was investigated.