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.

H2S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway.

Activating programmed cell death by delivering hydrogen sulfide (H2S) has emerged as a promising strategy for tumor therapy. Oridonin serves as a lead compound for drug development due to its unique scaffold and wide-ranging biological effects, especially its antitumor properties. Based on the previous structure-activity relationship studies, 33 novel 1-O/14-O H2S-releasing oridonin derivatives were synthesized. Particularly, 11a exhibited the most potent antiproliferative activity, effectively inhibiting colony formation, migration and invasion in both MCF-7 and MIA-PaCa-2 cells. It also inhibited the PI3K/AKT pathway to regulate the expression of Bax and Bcl-2, thereby initiating the Caspase cascade to activate mitochondrial mediated apoptosis. Furthermore, 11a suppressed tumor growth in breast cancer syngeneic models with no apparent toxicity.

Peniapyrones A-I, Cytotoxic Tricyclic-Fused α-Pyrone Derivatives from an Endophytic Penicillium brefeldianum F4a.

Five cyclopenta[d]pyrano[4,3-b]pyran-1,7(6H)-dione 6/6/5-fused tricyclic ring system containing metabolites peniapyrones A-E (1-5), and four previously undescribed cyclopenta[4,5]furo[3,2-c]pyran-1-one 6/5/5-fused tricyclic ring system containing compounds peniapyrones F-I (6-9), were isolated from the endophytic Penicillium brefeldianum F4a. Their structures, including absolute configurations, were determined through spectroscopic analysis and quantum chemical calculations. Peniapyrones D (4) and E (5) were a pair of diastereoisomers. Compounds 1, 3, and 5-9 showed cytotoxic activity against AsPC-1, CRL-2234, and MCF-7 cancer cell lines. Compounds 1, 3, 6, 8, and 9 inhibited the Kirsten rat sarcoma viral oncogene homologue (KRAS) mutant AsPC-1 cell line.

Design and synthesis of 6,20-epoxy A-ring modified oridonin derivatives with antitumor activity through extrinsic and mitochondrial pathways.

Oridonin is an antitumor ent-kaurane diterpenoid that medicinal chemists have been paying close attention to in recent years. Herein, a novel 6,20-epoxy A-ring modified oridonin derivative 2 was obtained by a 6-step synthesis. A series of 14-O derivatives of 2 (EpskA1-EpskA24) were synthesized to further enhance the activity. Based on their cytotoxicity against MCF-7, A549 and L-02 cells, EpskA9, EpskA10 and EpskA21 were chosen for further screening to obtain a wider antitumor spectrum. Collectively, EpskA21 showed the most potent antiproliferative activity, inhibiting proliferation and migration, and inducing apoptosis and cell cycle arrest in MCF-7 and MIA-PaCa-2 cells. With the help of network pharmacology analysis, apoptosis-related proteins were selected and further tested by western blot assay. The inhibition of PI3K/AKT and an increase in the levels of Bax/Bcl-2 ratio, Cyt-C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP was observed, indicating that EpskA21 induced apoptosis through the mitochondrial pathway. Given that an increase in DR5 expression and activated Caspase-8 were also observed, the extrinsic apoptosis pathway might also be related to the antitumor effect.

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.

Study on the chemical components and anti-neuroinflammatory activity of the roots of Clausena excavate Burm. f.

The ethanol extract of the roots of Clausena excavata gave two previously undescribed coumarins, clauexcatin A (1) and clauexcatin B (2), as well as a pair of new isomers, trans/cis-clauexcatin C (3a, 3b), along with thirty known compounds. Among these, compound 33 was isolated from this genus for the first time. The structures of these compounds were elucidated based on their physicochemical properties and spectroscopic data. The anti-neuroinflammatory activities were assessed using LPS-activated BV-2 microglial cells. Compounds 6, 8, 17, 24, 29, and 30 exhibited significant inhibition of nitric oxide release in a dose-dependent manner, with their inhibitory effects being 1.2 to 10.9 times greater than that of the positive control (minocycline).

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.

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.

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.

Two new iridoid glycosides from Odontites vulgaris.

Two new iridoid glycosides, named 3'-O-benzoyl-dolichocymboside D (1) and dolichocymboside E (2), along with ten known glycosides (3-12), were isolated from the ethanol extract of the whole plants of Odontites vulgaris Moench. The structures of the isolated compounds were elucidated by 1D and 2D NMR and HR-ESI-MS spectra and by comparison with those reported in the literature. This is the first report on compounds 11 and 12 isolated from the family Scrophulariaceae, and compounds 8-10 were isolated from the genus Odontites.

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.

Cephaloliverols A and B, two sterol-hybrid meroterpenoids from Cephalotaxus oliveri.

Cephaloliverols A (1) and B (2), two meroterpenoids based on a sterol and an abietane diterpene possessing a dioxane ring, were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures were established by spectroscopic analysis and quantum chemical calculation. 1 and 2 represent the first sterol-hybrid meroditerpenoids. The two compounds and their precursors decreased NO production in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages.

Cephalotaxine-type and homoerythrina-type alkaloids with antiproliferative effects from Cephalotaxus fortunei.

Twenty-two cephalotaxine-type and ten homoerythrina-type alkaloids, including seven previously undescribed ones, were isolated from the twigs and leaves and the seed kernels of Cephalotaxus fortunei. Their structures were established by spectroscopic analysis, single crystal X-ray diffraction, and ECD calculation methods. Cephalofortunine A ß-N-oxide (1) is the first nitrogen-oxidized homoerythrina-type alkaloid. The isolated compounds were evaluated for their in vitro antiproliferative effects against two human leukemia cell lines (THP-1 and K562). All compounds showed different levels of antiproliferation in THP-1 and K562 cells with GI50 values of 0.24-29.55 µM. Hainanensine (31) was the most active against two cancer cell lines with GI50 values of 0.24 ± 0.07, and 0.29 ± 0.01 µM, respectively.

(±)-Pheharmines A-B, two pairs of racemic alkaloids with a morpholino[4,3,2-hi]ß-carboline core, from the roots of Peganum harmala.

Two pairs of unprecedented ß-carboline-phenylpropanoid heterogeneous alkaloids, (±)-pheharmines A-B (1-4), characterized by a morpholino[4,3,2-hi]ß-carboline core with two chiral centers, were isolated from the roots of Peganum harmala. The structures, including their absolute configurations, were identified using spectroscopic analyses and electronic circular dichroism (ECD) calculations. The biosynthetic hypothesis for the formation of pheharmines A-B was proposed. Compounds 1-4 exhibited moderate cytotoxic activities against HL-60 cell lines.

Design and synthesis of chromone-nitrogen mustard derivatives and evaluation of anti-breast cancer activity.

Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC50 values of 1.83 and 1.90 µM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.

Anti-breast cancer sinomenine derivatives via mechanisms of apoptosis induction and metastasis reduction.

Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of Sinomenium diversifolius (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted in vitro and in vivo. In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid 7Cc exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC50 (0.82 µM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that 7Cc could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, 7Cc also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.

[Isoquinoline alkaloids from two species of Thalictrum genus plants].

The chemical constituents from the roots of Thalictrum cultratum and T. baicalense were investigated. By various isolation methods, such as silica gel, aluminium oxide, ODS, and Sephadex LH-20 column chromatographies, and semi-preparative HPLC, 11 simple isoquinoline alkaloids were isolated from the ethanol extract of the roots of these two plants, including a new compound, named dehydrothalflavine(1), and ten known ones(2-11): N-methylcorydaline(2), N-methylthalidaldine(3), thaliflavine(4), oxyhydrastinine(5), noroxyhydrastinine(6), dimethoxyisoquinolone(7), thalactamine(8), dehydronoroxyhydrastinine(9), 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(10), and isopicnarrhine(11). Their structures were elucidated on the basis of HR-ESI-MS and 1 D and 2 D NMR techniques. Compound 1 was a new isoquinoline alkaloid. Compound 11 was obtained from Tha-lictrum plant for the first time. All compounds did not show cytotoxic activities against HL-60, U937, HCT116, Caco-2, and HepG2 cancer cell lines.

Discovery of ß-carboline-(phenylsulfonyl)furoxan hybrids as potential anti-breast cancer agents.

The cytotoxicity properties of the ß-carboline alkaloids have been broadly investigated. However, the potential application of ß-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty ß-carboline-(phenylsulfonyl)furoxan hybrids (11a-j, 12a-j and 13a-j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 µM) and MDA-MB-231 (IC50 = 0.62 µM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.