Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree (Platanus occidentalis) represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun-N-terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.
The first phytochemical investigation of the twig extract of Uvaria leptopoda resulted in the isolation and identification of three new tetrahydroxanthene-1,3(2H)-diones, uvarialeptones A-C, two new oxidized hexadiene derivatives, uvarialeptols A and B, together with ten known compounds. Their structures were elucidated by spectroscopic techniques and mass spectrometry. Uvarialeptones A and B were unprecedented tetrahydroxanthene-1,3(2H)-dione dimers which exhibited a cyclobutane ring via [2 + 2] cycloaddition from uvarialeptone C and 9a-O-methyloxymitrone, respectively. The structure of uvarialeptone A was confirmed by X-ray diffraction analysis using Mo Kα radiation. Compound 3 inhibited NO production at an IC50 value of 6.7 ± 0.1 μM.
Eugeniifoline (1), a pentacyclic indole alkaloid with a five-membered ring E, was isolated for the first time as a natural product from the stem-bark extract of Leuconotis eugeniifolia. Eugeniifoline (1) was previously reported as a synthetic product from a diversity-enhanced extract, but with the configuration at C-21 reported as S (1a). The configuration at C-21 was revised to R as shown in 1, based on the NOE data, GIAO NMR calculations, and DP4+ probability analysis, as well as the TDDFT-ECD method.
Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 μM, respectively.
Cinnamomum cassia Presl (Cinnamon) has been widely cultivated in the tropical or subtropical areas, such as Yunnan, Fujian, Guandong, and Hainan in China, as well as India, Vietnam, Thailand, and Malaysia. Four new glycosides bearing apiuronic acid (1, 4, 6, and 7) and their sodium or potassium salts (2, 3, and 5), together with 31 known compounds, were isolated from a hot water extract of the bark of C. cassia via repeated chromatography. The structures of the new compounds (1-7) were determined by NMR, IR, MS, and ICP-AES data and by acid hydrolysis and sugar analysis. This is the first report of the presence of apiuronic acid glycosides. Some of the isolates were evaluated for their analgesic effects on a neuropathic pain animal model induced by paclitaxel. Cinnzeylanol (8), cinnacaside (9), kelampayoside A (10), and syringaresinol (11) showed analgesic effects against paclitaxel-induced cold allodynia.
Cancer is often associated with an aberrant increase in tubulin and microtubule activity required for cell migration, invasion, and metastasis. A new series of fatty acid conjugated chalcones have been designed as tubulin polymerization inhibitors and anticancer candidates. These conjugates were designed to harness the beneficial physicochemical properties, ease of synthesis, and tubulin inhibitory activity of two classes of natural components. New lipidated chalcones were synthesized from 4-aminoacetophenone via N-acylation followed by condensation with different aromatic aldehydes. All new compounds showed strong inhibition of tubulin polymerization and antiproliferative activity against breast and lung cancer cell lines (MCF-7 and A549) at low or sub-micromolar concentrations. A significant apoptotic effect was shown using a flow cytometry assay that corresponded to cytotoxicity against cancer cell lines, as indicated by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. Decanoic acid conjugates were more potent than longer lipid analogues, with the most active being more potent than the reference tubulin inhibitor, combretastatin-A4 and the anticancer drug, doxorubicin. None of the newly synthesized compounds caused any detectable cytotoxicity against the normal cell line (Wi-38) or hemolysis of red blood cells below 100 μM. It is unlikely that the new conjugates described would affect normal cells or interrupt with cell membranes due to their lipidic nature. A quantitative structure-activity relationship analysis was performed to determine the influence of 315 descriptors of the physicochemical properties of the new conjugates on their tubulin inhibitory activity. The obtained model revealed a strong correlation between the tubulin inhibitory activity of the investigated compounds and their dipole moment and degree of reactivity.
Phytochemical investigations of the twig and leaf extracts of Goniothalamus tortilipetalus resulted in the isolation and identification of two new alkaloids, goniotortiline (1) and goniotortilactam (2), three new styryl lactone derivatives, goniotortilactone (3) and goniotortilols A (4) and B (5), and 25 known compounds. Their structures were elucidated by spectroscopic methods and HRESITOFMS data. Compounds 5, 13, 15, 16, 22, and 30 inhibited nitric oxide (NO) production with IC50 values ranging from 8.7 ± 0.1 to 17 ± 1 μM, revealing stronger effects than the standard drug, dexamethasone (IC50 16.9 ± 2.2 μM), and compound 30 possessed the most potent NO production inhibition. Compounds 12 and 29 demonstrated notable efficacy in enhancing glucose consumption with IC50 values of 77 ± 4 and 66 ± 4 μM, respectively, while their glucose uptakes were 1.7- and 2-fold, respectively.
The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus, which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.
In the search of new inhibitors for human coronavirus (HCoV), we screened extracts of endemic Annonaceae plants on an assay using a cellular model of Huh-7 cells infected with the human alphacoronavirus HCoV-229E. The EtOAc bark extract of the rare Southeast Asian plant Neo-uvaria foetida exhibited inhibition of HCoV-229E and SARS-CoV-2 viruses with IC50 values of 3.8 and 7.8 μg/mL, respectively. Using LC-MS/MS and molecular networking analysis guided isolation, we discovered two new labdane-type diterpenoids, 8-epi-acuminolide (1) and foetidalabdane A (4), and three known labdane diterpenoids, acuminolide (2), 17-O-acetylacuminolide (3), and spiroacuminolide (5). A new norlabdane diterpene, 16-foetinorlabdoic acid (6), was also isolated and identified. Excluding compounds 5 and 6, all other metabolites were active against the virus HCoV-229E. Terpenoids 1 and 4 presented antiviral activity against SARS-CoV-2 with IC50 values of 63.3 and 93.5 μM, respectively, indicating lower potency. Additionally, virological assays demonstrated that compounds 1, 2, and 3 exert antiviral effects against Zika virus by specifically interfering with the late stage of its infectious cycle with IC50 values of 76.0, 31.9, and 14.9 μM, respectively.