Journal of Natural Products 最新文献

Pentavalent antimonials are the first-line treatment for localized cutaneous leishmaniasis. However, they have disadvantages such as their elevated toxicity, high costs, and parenteral application. Plant-derived compounds may be an alternative treatment against this disease. Previous in vitro studies have shown that (3S)-16,17-didehydrofalcarinol (1), a polyacetylene oxylipin isolated from Tridax procumbens, is active against Leishmania mexicana. We have analyzed the mechanism of action of compound 1, evaluating reactive oxygen species production, apoptosis of L. mexicana, cytotoxicity in murine macrophages, and its efficacy in controlling the disease progression and parasite load when applied topically in C57BL/6 mice infected with L. mexicana. Results show that parasites incubated with 1.6 μM compound 1 significantly increased reactive oxygen species production (p ≤ 0.05). The percentage of apoptosis also increased significantly (p ≤ 0.05) and did not affect the viability of macrophages. The application of the topical formulations with 0.5% and 0.75% compound 1 for 7 weeks reduced disease progression and parasite load. We demonstrate that compound 1 generates the death of L. mexicana by apoptosis through reactive oxygen species production. We conclude that compound 1 can be used a possible alternative treatment for localized cutaneous leishmaniasis, enabling a less painful and more accessible therapy.

We discovered new natural products pinocicolins A (1) and B (2) from Penicillium pinophilum and determined the stereochemistry of these compounds by degradation and derivatization. Compound 1, containing two isocyanide groups, exhibited bacteriostatic activity against Gram-positive bacteria depending upon its copper-chelating activity. The biosynthesis of compound 1 was reconstructed in Aspergillus nidulans by heterologous expression of multidomain isocyanide synthase-nonribosomal peptide synthetase Pp_crmA and efflux pump Pp_crmE. This is the first report of the heterologous production of a fungal diisocyanide natural product, highlighting the multistep catalysis of CrmA family enzymes.

Seven pairs of new epimers, microsphazaphilones A-G (1, 3, 5, 7, 9, 11, and 13) and epimicrosphazaphilones A-G (2, 4, 6, 8, 10, 12, and 14), were isolated and identified from the fermentation of a marine-derived fungus Microsphaeropsis arundinis P1B. Their structures, including the absolute configurations, were determined by NMR and MS data analysis, comparison of experimental and calculated electronic circular dichroism (ECD) curves, and dimolybdenum tetraacetate induced ECD. Microsphazaphilones A-G and epimicrosphazaphilones A-G represent the sclerotiorin-type azaphilones with a rare γ-lactone or a tetrahydrofuran fragment at the end of the branched C₇ side chain at the C-3 position of the pyranoquinone core skeleton. Among them, compound 2 demonstrated the strongest anti-inflammatory activity that inhibited the expression of multiple inflammatory factors in LPS-induced Raw264.7 cells, possibly through the inhibition of the Erk1/2 MAPK signaling pathway.

The first syntheses of the Phomopsis-isolated natural products phochrodines A-C are reported. Functional group manipulations on a key 5H-chromeno[4,3-b]pyridine intermediate, itself synthesized from intramolecular Suzuki-Miyaura coupling, enabled facile and high-yielding syntheses of all three natural products. Additionally, sufficient material was generated to enable detailed pharmacological profiling of each compound. Preliminary drug metabolism and pharmacokinetic (DMPK) experiments and ancillary pharmacology screening revealed phochrodine C (3) as an attractive scaffold for further modification, particularly for medicinal chemists working in the antidepressant space.

Dibenzopyrrocoline alkaloids, found in lauraceous and hernandiaceous plants, have been studied since the 1950s. The absolute configuration of these alkaloids, including cryptaustoline, has been a topic of debate due to conflicting studies. Having in our laboratory some authentic samples of dibenzopyrrocoline-type Cryptocarya alkaloids, we decided to reinvestigate their absolute configuration using modern spectroscopic techniques along with TDDFT calculations. The NMR reinvestigation of the authentic sample of cryptowolinol led us to revise its relative configuration using ML-J-DP4 and DP4+ analyses. Moreover, the absolute configuration of all dibenzopyrrocoline alkaloids reported to date benefitted from a complete re-evaluation based on a comparison with TDDFT-SR and TDDFT-ECD predictions leading to a unified absolute configuration. At last, this patrimonial reinvestigation unveiled a historical sample corresponding to a heretofore unpublished dibenzopyrrocoline alkaloid, which we named isocryptaustoline. The reisolation of this molecule from the total alkaloid extract of Cryptocarya oubatchensis makes it a genuine natural product.

The 1,3-oxazin-6-one-containing spinoxazines A and B (2 and 3, respectively) have been isolated from the marine-derived Streptomyces spinoverrucosus strain SNB-048 and, by another group, from the Solar Saltern-derived Streptomyces sp. KMF-004. Two distinct pathways have been proposed for the conversion of the co-occurring pyrrolizidine alkaloid bohemamine D (1) into compound 3. Here, we report that the readily prepared compound 10, which embodies the 2-hydroxy-1,2-dihydro-3H-pyrrol-3-one core of bohemamine D (1) and is the bis-O-methyl ether of the alkaloid discoipyrrole C, is converted into 1,3-oxazin-6-one 11 on heating at elevated temperatures in air. The mechanism of this conversion was studied using density functional theory and the biosynthetic implications of it are discussed. The photochemical reaction of compound 10 in the presence of oxygen is also detailed and, again, the possible biosynthetic implications of the resulting conversion are considered.

Natural hydroxycinnamic acid amides (HCAAs) and riparins offer significant health benefits. However, their extraction from natural sources is difficult, and traditional synthetic methods remain wasteful, raising the need for more efficient alternatives. In this work, a two-step chemo-enzymatic flow method for the efficient esterification and amidation of phenolic acids was developed and successfully applied to the synthesis of riparin derivatives and HCAAs. The flow Fischer esterification was optimized using vanillic acid as a model starting material and SiliaBond Tosic Acid (SCX-3) as an immobilized acid catalyst, achieving a quantitative yield in a short residence time. The following amidation step, catalyzed by immobilized Candida antarctica lipase B, was optimized in toluene, leading to the desired amides. The synthesized compounds were evaluated for their radical scavenging, antibacterial, and antileishmanial properties. Overall, this work disclosed a novel approach for the efficient synthesis of riparin derivatives and HCAAs with interesting biological properties.

Sealgamide (1), a new antitrypanosomal lipopeptide, was isolated from a marine Okeania sp. cyanobacterium. Elucidation of its structure was challenging due to signal overlap caused by conspicuous rotamers but was ultimately achieved through partial hydrolysis and subsequent spectroscopic analyses. Sealgamide (1) exhibited moderate antitrypanosomal activity against Trypanosoma brucei rhodesiense (IC₅₀ 2.9 μM) while showing no antimalarial activity (IC₅₀ > 25 μM) or cytotoxicity (IC₅₀ > 30 μM). Furthermore, we discovered that an artificial C-terminal methyl ester analogue (2) exhibited notably enhanced antiparasitic activity.

An azaphilone, 6,7-iso-felinone A (2), was isolated from Diaporthales sp. KT3922 along with the known felinone A (1). While compound 2 exhibited weak Cotton effects, its naphthoate derivative (2a) displayed pronounced Cotton effects, enabling the determination of its absolute configuration through electronic circular dichroism (ECD) spectral analysis. Interestingly, the spectroscopically derived relative structure of compound 2 proved identical to previously reported hypoillexidiol (3) and xylariphilone (4). However, substantial differences in ¹H nuclear magnetic resonance data among these compounds warranted structural reinvestigation of the entire series, including the structurally related fungal metabolites, fusaraisochromenone (5) and aspergillusone C (6). Comparative analysis revealed identical relative configurations of compounds 1, 3, 4, and 5. Furthermore, compounds 1 and 3 were determined to have an identical absolute configuration, whereas the absolute configuration of compound 4 remained inconclusive due to a significant mismatch in its ECD spectral profile compared to compound 1. Compound 5 was identified as the enantiomer of compounds 1 and 3. Additionally, we discussed the stereochemistry of the 6,7-cis-diol isomer, aspergillusone C (6).

Seven new sesquiterpene hydroquinone/quinone (SQ) meroterpenoids, cinerols L-R (1-7), along with four known analogues (8-11), were identified from a marine sponge, Dysidea cinerea, collected from the shore of the Xisha Islands in the South China Sea. The structures of 1-7 were established by the analysis of NMR, high-resolution MS, and comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Cinerol L (1) is particularly noteworthy, as it features a 5H-pyrrolo[1,2a]-benzimidazole moiety modified by an ethyl sulfonate, while cinerols N (3) and O (4) possess a unique acetyl-substituted hydroquinone moiety. Cinerols L-R (1-7) were evaluated for their inhibitory activity against inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE₂) with IC₅₀ values of 5-20 μM in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages. Furthermore, the potent inhibitory activity on inflammatory cytokines of 4 prompted us to evaluate its effect on the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, a critical pathway that contributes to the inflammatory responses. Cinerol O (4) was unveiled to inhibit cyclooxygenase-2 (COX-2) expression and the production of inflammatory cytokines via suppressing the expression of NF-κB and MAPKs in LPS-induced RAW 264.7 macrophages.