Synthesis of sinomenine derivatives with potential anti-leukemia activity.

In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

α-Glucosidase Inhibitory Components from Garcinia pedunculata Fruits.

From Garcinia pedunculata Roxb. fruits, two undescribed aromatic compounds including a benzofuran and a depsidone derivative, and a new natural product, together with four known compounds were isolated. Through the analysis of spectroscopic data, high resolution mass spectrum and calculated nuclear magnetic resonance, their structures were determined. The α-glucosidase inhibitory activity of the isolates was evaluated. And compound 3 exhibited a moderate inhibitory effect on α-glucosidase. The molecular docking of compound 3 was performed to elucidate the interaction with α-glucosidase.

New aporphine alkaloids with antitumor activities from the roots of Thalictrum omeiense.

Two new aporphine alkaloids, 6aR-2'-(3-oxobutenyl)-thaliadin (1) and N-methylthalisopynine (2), along with ten known analogs (3-12), were isolated from the roots of Thalictrum omeiense W. T. Wang et S. H. Wang. Their structures were determined by extensive spectroscopic and X-ray crystallographic analyses. Compounds 1-7 and 9-12 were tested for their antiproliferative effects in vitro against two human cancer cell lines (A549 and MCF-7). Among them, compounds 1, 3, and 7 exhibited moderate inhibitory activity against the tested cell lines with IC50 values ranging from 23.73 to 34.97 µM.

ß-Carboline alkaloids from the roots of Peganum harmala L.

This study reports the isolation of four new ß-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these compounds, 1 and 2 were characterized as rare ß-carboline-quinazoline dimers exhibiting axial chirality. Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring, and compound 4 was a novel annomontine ß-carboline. The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations. The biosynthetic pathways of 1-3 were proposed. Additionally, the cytotoxicity of some isolates against four cancer cell lines (HL-60, A549, MDA-MB-231, and DU145) was evaluated. Notably, compound 4 exhibited significant cytotoxicity against HL-60, A549, and DU145 cells with IC50 values of 12.39, 12.80, and 30.65 µmol·L-1, respectively. Furthermore, compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC50 value of 17.32 µmol·L-1.

Divergent Synthesis of Quinolines: Exploiting the Duality of Free Radicals.

Herein, we present a green scheme for the divergent synthesis of two polysubstituted quinolines from a singular substrate via exploiting free-radical duality. Photocatalytically generated imine radicals produce 3,4-disubstituted quinolines via a novel rearrangement in the presence of an inorganic base. Alternatively, they react in the presence of an organic base to furnish 2,3-disubstituted quinolines. Mechanism studies support the hypothesis that the electrophilic/nucleophilic bias of free radicals can be adjusted by altering the reaction conditions.

Antiproliferative polycyclic polyprenylated acylphloroglucinols from Garcinia paucinervis.

Bioassay-guided isolation of the stems of Garcinia paucinervis led to one new adamantane-type polycyclic polyprenylated acylphloroglucinols (PPAPs), (-)-garpauvinin A (1), and four known analogues (2-5). The structure and absolute configuration of 1 was established via spectroscopic techniques and ECD method. All the isolates displayed moderate antiproliferative activity against HL-60, PC-3 and Caco-2 human cancer cell lines with IC50 values ranging from 0.81 to 19.92 µM, and exhibited low toxicity on WPMY-1 normal human cells, showing selectivity between normal and malignant prostate cells. The biosynthetic pathways of the isolated PPAPs were proposed.

Diterpenolignans and cephalotane diterpenoids from Cephalotaxus oliveri mast. with antitumor activity.

Four undescribed naturally diterpenolignans, and two cephalotane diterpenoids, along with seven known compounds, including two pairs of enantiomers, were isolated from the twigs and leaves of Cephalotaxus oliveri Mast. Their structures were elucidated via spectroscopic data interpretation, chiral-phase HPLC analysis, NMR calculations, and electronic circular dichroism analysis. All the isolated compounds were evaluated for their cytotoxic activities against three kinds of human tumor cell lines. Among them, compound 8 exhibited the most potent activities against MCF-7, HepG2 and A549 cell lines with IC50 values of 2.83, 4.75 and 2.77 µM, respectively.

Cytotoxic xanthones from Garcinia pedunculata fruits.

Eight previously undescribed and seven known xanthones were isolated from the fruits of Garcinia pedunculata Roxb. The structures were identified by a variety of spectroscopic methods as well as by comparison with the literature. The isolates showed appreciable cytotoxicity against three human tumor cell lines (HepG2, A549, and MCF-7). Pedunculaxanthone G exhibited inhibitory activities with IC50 values of 12.41, 16.51, and 15.45 µM against the cancer cell lines and induced cell apoptosis in HepG2 cells.

Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 µM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Design and Synthesis of Brefeldin A-Isothiocyanate Derivatives with Selectivity and Their Potential for Cervical Cancer Therapy.

Brefeldin A has a wide range of anticancer activity against a variety of tumor cells. Its poor pharmacokinetic properties and significant toxicity seriously hinder its further development. In this manuscript, 25 brefeldin A-isothiocyanate derivatives were designed and synthesized. Most derivatives showed good selectivity between HeLa cells and L-02 cells. In particular, 6 exhibited potent antiproliferative activity against HeLa cells (IC50 = 1.84 µM) with no obvious cytotoxic activity to L-02 (IC50 > 80 µM). Further cellular mechanism tests indicated that 6 induced HeLa cell cycle arrest at G1 phase. Cell nucleus fragmentation and decreased mitochondrial membrane potential suggested 6 could induce apoptosis in HeLa cells through the mitochondrial-dependent pathway.

[Lignans from stems and leaves of Cephalotaxus fortunei (â ¡)].

The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-ß-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.

A photoactivated H2S donor based on a coumarin structure with real-time monitoring capability.

Attaining controlled, biocompatible H2S donors poses significant challenges. We developed Bhc-TCN-Ph, a photoactivated H2S donor derived from 6-bromo-7-hydroxycoumarinmethyl thiocarbonate. Upon 365 nm light exposure, COS is released, generating H2S and coumarin fluorescence for visualization. This process produces no electrophilic by-products. In vitro evaluations reveal good cytochemical and cytocompatibility characteristics.

5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione derivatives of brefeldin A: Design, synthesis and cytotoxicity in MDA-MB-231 human breast cancer cells.

27 novel 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione derivatives of brefeldin A were designed and synthesized to make them more conducive to the cancer treatment. The antiproliferative activity of all the target compounds was tested against six human cancer cell lines and one human normal cell line. Compound 10d exhibited nearly the most potent cytotoxicity with IC50 values of 0.58, 0.69, 1.82, 0.85, 0.75, 0.33 and 1.75 µM against A549, DU-145, A375, HeLa, HepG2, MDA-MB-231 and L-02 cell lines. Moreover, 10d inhibited metastasis and induced apoptosis of MDA-MB-231 cells in a dose-dependent manner. The potent anticancer effects of 10d were prompted based on the aforementioned results, the therapeutic potential of 10d for breast cancer was worth further exploration.

Marine-Derived Lead Fascaplysin: Pharmacological Activity, Total Synthesis, and Structural Modification.

Fascaplysin is a planar structure pentacyclic alkaloid isolated from sponges, which can effectively induce the apoptosis of cancer cells. In addition, fascaplysin has diverse biological activities, such as antibacterial, anti-tumor, anti-plasmodium, etc. Unfortunately, the planar structure of fascaplysin can be inserted into DNA and such interaction also limits the further application of fascaplysin, necessitating its structural modification. In this review, the biological activity, total synthesis and structural modification of fascaplysin will be summarized, which will provide useful information for pharmaceutical researchers interested in the exploration of marine alkaloids and for the betterment of fascaplysin in particular.

Apoptotic effects of phenols from the twigs and leaves of Garcinia nujiangensis.

In order to find potential agents for treating cancer disease in naturally occurring compounds, we conducted a systematic phytochemical investigation on the endemic species of Garcinia nujiangensis. Three new biphenyl derivatives (1-3) and one new polycyclic polyprenylated benzophenone (4), together with four known benzophenone analogues (5-8), have been isolated from the CH2Cl2 extract of the twigs and leaves of G. nujiangensis. Their structures were determined by detailed spectroscopic analyses and comparison with structurally related known analogues. Experimental and calculated ECD method was used to determine the absolute configuration of 1 and 4. Moreover, compounds 5-7 were isolated for the first time from this species. The cytotoxicities of the new compounds were evaluated using HL-60, HepG2, and A549 human cancer cell lines. Compound 4 showed more significant antiproliferative effects against HepG2 cells with an IC50 value of 11.38 ± 0.79 µM than that of three biphenyl derivatives. The morphological features of apoptosis were evaluated in 4-treated HepG2 cells. Compound 4 effectively prevented the cell cycle progression of HepG2 cells in G2 phase. Additionally, western blot analysis indicated that treatment of 4 on HepG2 cells led to decreased expression of anti-apoptotic Bcl-2 and pro-Caspase-3, and increased protein expression of both pro-apoptotic Bax and cleaved PARP with reference to ß-actin. Overall, our results suggested that the active polycyclic polyprenylated benzophenone derivatives in the twigs and leaves of G. nujiangensis can be used as a valuable source of bioactive compounds for the pharmaceutical industry.

The GSK3ß/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors.

Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3ß activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3ß and downregulate Mcl-1. Inactivation of GSK3ß through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3ß/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3ß/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.

Triterpene Derivatives from Garcinia oligantha and Their Anti-Cancer Activity.

Phytochemical investigations of leaves and twigs from Garcinia oligantha Merr. resulted in the isolation of five undescribed triterpene derivatives (1-5) and six known analogs (6-11). Their structures were determined based on extensive spectroscopic data and high-resolution mass spectra analyses. Compounds 1-11 were tested for their in vitro cytotoxicity against three human cancer cell lines (HeLa, HepG-2, and MCF-7). Compounds 1, 2, 8, and 11 exhibited broad and significant cytotoxicity against the tested cell lines with IC50 values ranging from 5.04 to 21.55 µM. Compounds 5 and 9 showed cytotoxicity against HeLa and MCF-7 with IC50 values ranging from 13.22 to 19.62 µM. The preliminary structure-activity relationship for the 11 isolated compounds is also discussed.

Effect of CYP3A inducer/inhibitor and licorice on hepatotoxicity and in vivo metabolism of main alkaloids of Euodiae Fructus based on UPLC-Q-Exactive-MS.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism, but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing. AIM OF THE STUDY: The poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP). MATERIALS AND METHODS: Rats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and Orthogonal Partial Least Squares Discriminant Analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups. RESULTS: EF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group. CONCLUSION: Licorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity.

Cytotoxic alkaloids from the fruit pods of Macleaya microcarpa.

19 compounds, including seven previously undescribed alkaloids ((-)-macleayin K (1), (+)-macleayin K (2), macleayin M (3), macleayin N (4), macleayin L (5), macleayin O (6), oxohydrastinine A (7), one new natural product (8), and 11 known compounds, were isolated from the fruit pods of Macleaya microcarpa. Their structures were defined based on NMR, HRESIMS, and electronic circular dichroism (ECD) data. A network pharmacology approach combined with molecular docking and in vitro validation was performed to determine the bioactivity, key targets of the 19 compounds against breast cancer (BC) and cervical cancer (CC). EGFR and PIK3CA could become potential therapeutic targets based a network pharmacology. Moreover, molecular docking suggested that the 19 compounds combined well with EGFR and PIK3CA, respectively. Their cytotoxicity of selected compounds was tested against the MCF-7 and HeLa cells, and the preliminary structure-activity relationship is discussed. Compounds 1 (IC50: 6.00 µM) and 2 (IC50: 6.82 µM) exhibited strong inhibitory activity against the HeLa cells and are worthy of further study.

Stilbenes with potent cytotoxicity from the seedcases of Paeonia suffruticosa Andrews.

Stilbenes (based on the 1,2-diphenylethylene skeleton) are a class of plant polyphenols with rich structural and bioactive diversity. Twenty-six stilbenes, including five undescribed compounds (7,8-dioxy-4,3',5'-trihydroxystilbene, trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B), were isolated from the seedcases of Paeonia suffruticosa Andrews. Their structures were elucidated by spectroscopic analyses and comparison with previously reported data. The absolute configurations of trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B were assigned from their respective electronic circular dichroism (ECD) spectra. Additionally, the structures of known compounds suffruticosols A, B and rockiol B were revised and the absolute configurations of them, and along with (+)-davidiol A, were also further determined by ECD. The isolated compounds, trans-gnetin H, cis-gnetin H and suffruticosol E, were found to have potent cytotoxicity against the DU-145 and MDA-MB-231 cell lines with IC50 values of 4.89-8.61 µM. The preliminary antitumor structure-activity relationship of these stilbenes is discussed as well.