Fusarium solani PQF9 Isolated from Podocarpus pilgeri Growing in Vietnam as a New Producer of Paclitaxel.

Endophytic fungi are known as an alternative promising source of anticancer drug, paclitaxel, however fungi inhabiting in medicinal plant Podocarpus pilgeri and their paclitaxel production have not been reported to date. In the present study, a total of 15 culturable fungi classified into 5 genera, were successfully recovered from P. pilgeri collected in Vietnam. Screening fungal dichloromethane extracts for anticancer activity revealed that only PQF9 extract displayed potent inhibitory effects on A549 and MCF7 cancer cell lines with IC50 values of 33.9 ± 2.3 µg/mL and 43.5 ± 1.7 µg/mL, respectively. Through PCR-based molecular screening, the isolate PQF9 was found to possess 3 key genes involved in paclitaxel biosynthesis. Importantly, high-performance liquid chromatography quantification showed that fungal isolate PQF9 was able to produce 18.2 µg/L paclitaxel. The paclitaxel-producing fungus was identified as Fusarium solani PQF9 based on morphological and molecular phylogenetic analysis. Intensive investigations by chromatographic methods and spectroscopic analyses confirmed the presence of paclitaxel along with tyrosol and uracil. The pure paclitaxel had an IC50 value of 80.8 ± 9.4 and 67.9 ± 7.0 nM by using cell viability assay on A549 lung and MCF7 breast cancer cells. In addition, tyrosol exhibited strong antioxidant activity by scavenging 2, 2-diphenyl-picrylhydrazyl (DPPH) (IC50 5.1 ± 0.2 mM) and hydroxyl radical (IC50 3.6 ± 0.1 mM). In contrast, no biological activity was observed for uracil. Thus, the paclitaxel-producing fungus F. solani PQF9 could serve as a new material for large-scale production and deciphering paclitaxel biosynthesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01119-z.

Antiproliferative and antiinflammatory coxib-combretastatin hybrids suppress cell cycle progression and induce apoptosis of MCF7 breast cancer cells.

In our study, some newly synthesized aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of two apoptotic inducing agents celecoxib and combretastatin A-4 were found to have strong antiproliferative as well as antiinflammatory activities. Among these coxib-combretastatin hybrids, two lead compounds 8 and 6c simultaneously inhibited prostaglandin E2 (PGE2) production in LPS-activated murine macrophage RAW 264.7 cells and suppressed cell cycle progression of MCF7 cells at G2/M or G0/G1 phases, but only compound 8 induced apoptosis via caspase-3 activation. Both the lead compounds showed good docking energies with both protein targets COX-2 and tubulin in the molecule interaction modeling. The cis-diphenylethylene scaffold of celecoxib or combretastatin A-4 as well as functional groups such as the ethyl ester group and the sulfonamide could be considered as potential key features for the dual activity of studied compounds meanwhile the trimethoxybenzene remained the crucial characterization of the newly derived compounds of combretastatins.

Bioactive compounds from Physalis angulata and their anti-inflammatory and cytotoxic activities.

A new compound, physalucoside A (1), together with seven withanolides (2-8) and three flavonoids (9-11), were isolated from Physalis angulata L. (Solanaceae), a medicinal plant native to Vietnam. The chemical structures of these compounds were elucidated by one- and two-dimensional NMR spectra, high-resolution electrospray ionization mass spectrometry analyses, and chemical reactivity. The anti-inflammatory and cytotoxic activities of isolated compounds were also evaluated. These data suggest that the anti-inflammatory activity of P. angulata is due primarily to its withanolide content. This study demonstrates the potential of withanolides as promising candidates for the development of new anti-inflammatory drugs.

Cytotoxic dammarane-type triterpenoids from the leaves of Viburnum sambucinum.

Four new dammarane-type triterpenoids (1-4) and twelve known compounds (5-16) were isolated from the leaves of Viburnum sambucinum Reinw. ex Blume. Their structures were determined by spectral data analysis, including MS and 2D NMR. Cytotoxic activity evaluation in vitro against four cancer cell lines (KB, LU-1, HepG2 and MCF7) suggested that the octanor-dammarane derivatives were the main cytotoxic components of the leaves of V. sambucinum.

Isolation, anticancer potency, and camptothecin-producing ability of endophytic fungi isolated from Ixora chinensis.

Camptothecin (CPT) is an important alkaloid used for anticancer treatment. It is mainly produced by two endangered and overharvested Camptotheca acuminata and Nothapodytes nimmoniana plants. Endophytic fungi are promising alternative sources for CPT production. In the present study, fungi residing within explants of Ixora chinensis were isolated and their CPT-producing capability of their endophytes was verified via thin-layer chromatography, high-performance liquid chromatography, liquid chromatography/high resolution mass spectrometry, and nuclear magnetic resonance analyses and compared with standards. In addition, MTT and sulforhodamine B assays were selected to test the anticancer effect. The endophytic fungi collection of 62 isolates were assigned to 11 genera, with four common genera (Diaporthe, Phyllosticta, Colletotrichum, and Phomopsis) and seven less common genera (Penicillium, Botryosphaeria, Fusarium, Pestalotiopsis, Aspergillus, and Didymella). Moreover, the anticancer activity of extracts was assessed against human lung carcinoma (A549). Among eight potential extracts, only Penicillium sp. I3R2 was found to be a source of CPT, while the remaining seven extracts have not been discovered potential secondary compounds. Thus, other prominent endophytic fungi might be potential candidates of phytochemicals with anticancer properties.

Cinchonain Ia Shows Promising Antitumor Effects in Combination with L-Asparaginase-Loaded Nanoliposomes.

Cancer is among the leading causes of death worldwide, with no effective and safe treatment to date. This study is the first to co-conjugate the natural compound cinchonain Ia, which has promising anti-inflammatory activity, and L-asparaginase (ASNase), which has anticancer potential, to manufacture nanoliposomal particles (CALs). The CAL nanoliposomal complex had a mean size of approximately 118.7 nm, a zeta potential of -47.00 mV, and a polydispersity index (PDI) of 0.120. ASNase and cinchonain Ia were encapsulated into liposomes with approximately 93.75% and 98.53% efficiency, respectively. The CAL complex presented strong synergistic anticancer potency, with a combination index (CI) < 0.32 in two-dimensional culture and 0.44 in a three-dimensional model, as tested on NTERA-2 cancer stem cells. Importantly, the CAL nanoparticles demonstrated outstanding antiproliferative efficiency on cell growth in NTERA-2 cell spheroids, with greater than 30- and 2.5-fold increases in cytotoxic activity compared to either cinchonain Ia or ASNase liposomes, respectively. CALs also presented extremely enhanced antitumor effects, reaching approximately 62.49% tumor growth inhibition. Tumorized mice under CALs treatment showed a survival rate of 100%, compared to 31.2% in the untreated control group (p < 0.01), after 28 days of the experiment. Thus, CALs may represent an effective material for anticancer drug development.

Novel trans-caffeate hydrazide derivatives: synthesis, inhibition of nitric oxide (NO) production and molecular docking studies.

Eight new caffeyl hydrazide derivatives (4a-4h) were synthesised via a convenient esterification of caffeic acid with some substituted aryl acid hydrazides. The synthesised caffeyl derivatives were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages. The fluorobenzoylhydrazide derivatives 4f, 4 g and 4h were found to be the most powerful anti-inflammatory compounds with IC50 values ranging from 11.90 to 24.17 µM, which were more potent than the reference compound L-NMMA (IC50 32.8 µM). Additionally, synthesised compounds have been rationalised by using molecular docking studies which were performed in order to understand insights on the action mechanism of newly synthesised inhibitors against inflammatory mediator (iNOS). Obtained data indicate that compounds 4f, 4h, 4a and 4 g were observed to effectively bind to iNOS receptor with dock score values of -11.62, -10.81, -10.78 and -10.51 kcal/mol, respectively.

Chemical composition, anti-inflammatory and cytotoxic activity of essential oils from two Luvunga species (L. scandens and L. hongiaoensis) from Vietnam.

New essential oils (EOs) extracted from different parts of two Luvunga species (L. scandens and L. hongiaoensis) from Vietnam were investigated for their chemical composition, anti-inflammatory and cytotoxic activity. Sixty-nine total compounds were identified in the EOs by GC/MS. The major constituent of the leaf, fruit, and root EOs from L. scandens was ß-caryophyllene (71.5%, 63.0%, and 31.5% respectively). The main compounds in L. hongiaoensis EOs were ß-elemene (34.3% in leaf oil) and caryophyllene oxide (21.2% in root oil, 19.4% in stem oil). The EO from L. scandens fruits significantly inhibited nitric oxide production on LPS-induced RAW264.7 cells (IC50 = 37.95 ± 2.76 µg/mL). The EOs from L. hongiaoensis roots and L. scandens leaves and fruits exhibited cytotoxic activity against MCF-7, SK-LU-1, and HepG2 (IC50 from 49.74 ± 3.36 to 97.82 ± 8.61 µg/mL). This is the first report on L. hongiaoensis EOs and significantly complements the composition and bioactivity of L. scandens EOs.

Study on the Anticancer Activity of Prodigiosin from Variants of Serratia Marcescens QBN VTCC 910026.

Prodigiosin (Pg), a secondary metabolism produced by numerous bacterial species, is known as anticancer, antibacterial, antifungal, immunosuppressant, antioxidant, antimalarial properties. Pg has been tested for antitumor activity in many different cancer cell lines but studies in LU-1, KB cell lines, and tumor-bearing mice are still limited. In this study, Serratia marcescens QBN VTCC 910026 strain (GenBank: KX674054.1) was mutated using Ethyl Methanesulfonate (EMS) to increase the production of Pg. One strain known as EMS 5 was capable of increasing prodigiosin biosynthetic yield by 52% when compared to the wild-type strain. Red bacterial pigmented colonies containing Pg were collected from solid media, lysed with acetone, purified with toluene: ethyl acetate at a ratio of 9: 1 (v/v), and then used to evaluate the potential anticancer activity. The purity of Pg was confirmed using a high-performance liquid chromatography (HPLC) method which indicated a 98% rate. Pg chemical formula which was determined using 1H-NMR and 13C-NMR spectroscopy, confirmed as prodigiosin (Pg). Human breast cancer cell lines MCF-7, oropharyngeal cancer KB, and particularly lung cancer LU-1 in vitro were used to test the anticancer activity of purified Pg compound. It showed a strong inhibitory ability in all the cancer cell lines. Furthermore, the isolated Pg had capable of inhibiting tumor growth, the tumor volume decreased by 36.82%, after 28 days. The results indicated that the bacterial prodigiosin from variants Serratia marcescens QBN VTCC 910026 strain is an encouraging fragment suitable for therapeutic applications.

Chemical Constituents of Eupatorium japonicum and Anti-Inflammatory, Cytotoxic, and Apoptotic Activities of Eupatoriopicrin on Cancer Stem Cells.

Eupatorium japonicum Thunb. of the plant family Asteraceae is a popular traditional herb in Vietnam. However, its chemical constituents as well as bioactive principles have not been investigated yet. We investigated the phytochemistry of E. japonicum in Vietnam and isolated seventeen compounds (1-17) including phytosterols, terpenoids, phenolic acids, flavonoids, fatty alcohols, and fatty acids. They were structurally determined by MS and NMR analysis. Except for compounds 6 and 12, all the other compounds were identified for the first time from E. japonicum. Since many sesquiterpene lactones with α-methylene γ-lactone ring are reported as anti-inflammatory and anticancer agents, eupatoriopicrin (10), 1-hydroxy-8-(4,5-dihydroxytigloyloxy)eudesma-4(15),11(13)-dien-6,12-olide (11) were selected among the isolates for biological assays. Compound 10 was identified as the main bioactive sesquiterpene lactone of E. japonicum showing its potent anti-inflammatory and cytotoxic activity through inhibiting NO production and the growth of HepG2 and MCF-7 human cancer cell lines. For the first time, eupatoriopicrin (10) was demonstrated to strongly inhibit NTERA-2 human cancer stem cell (CSC) line in vitro. It is noticeable that the cytotoxicity of eupatoriopicrin against NTERA-2 cells is mediated by its apoptosis-inducing capability of 10 as demonstrated by the results of Hoechst 33342 staining, flow cytometry apoptosis analysis, and caspase-3 activity assays. The biological activities of the main bioactive constituents 1-7, 10, 12, and 15 supported the reported anti-inflammatory and anticancer properties of extracts from E. japonicum.

Garcinoxanthones SV, new xanthone derivatives from the pericarps of Garcinia mangostana together with their cytotoxic and antioxidant activities.

Xanthones (9H-xanthene-9-ones) are considered to be very promising compounds due to a variety of interesting biological and pharmacological activities. In this study, column chromatography of the methanol extract of the Garcinia mangostana L. pericarps resulted in the isolation of four new xanthones (garcinoxanthones SV, 1-4) and five known analogs including garcinone E (5), 11-hydroxy-1-isomangostin (6) mangostenone E (7), 1,3,6,7-tetrahydroxyxanthone (8), and α-mangostin (9). The structures of the new compounds were elucidated by NMR, HRESIMS, and ECD spectra. Compound 8 (1,3,6,7-tetrahydroxyxanthone) was found from the G. mangostana pericarps for the first time. All the isolated compounds (1-8) were evaluated for their 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity and cytotoxicity in vitro against three human cancer cell lines including SK-LU-1, MCF7, and HT-29 cell lines. Compounds 3, 5, and 8 exhibited significant DPPH scavenging capacity with IC50 values of 68.55, 63.05, and 28.45 µM, respectively, in comparison with ascorbic acid (IC50 = 48.03 µM). Compounds 5 and 8 showed moderate cytotoxic effects against the three human cancer cell lines with IC50 value ranges of 19.86-27.38 µM.

Triterpene glycosides from the Vietnamese sea cucumber Holothuria edulis.

From the MeOH extract of the Vietnamese sea cucumber Holothuria edulis, eight triterpene glycosides (1-8), including one new compound namely holothurin A5 (1), were isolated by using various chromatographic separations. Their structures were established by spectroscopic experiments including 1D, 2D NMR and HR-ESI-MS. Holothurin A5 (1) has a hydroperoxy group at C-25. To the best of our knowledge, this is the first report of this group in triterpene saponins obtained from sea cucumbers to date. In addition, the in vitro cytotoxicity against five human cancer cell lines (HepG2, KB, LNCaP, MCF7 and SK-Mel2) of all isolated compounds was also evaluated using SRB assays.

Chemical constituents of Oldenlandia pinifolia and their antiproliferative activities.

This study describes the chemical constituents of Oldenlandia pinifolia (Wall. Ex G. Don) Kuntze (synonym Hedyotis pinifolia Wall. Ex G. Don) and discusses their anti-proliferative activities. Thirteen compounds were isolated from the n-hexane, ethyl acetate and n-butanol extracts of whole plants O. pinifolia by chromatography method. Their structures were elucidated using MS and NMR analysis and compared with reported data. They are three anthraquinones, a carotenoid, two triterpenes, four iridoid glycosides and three flavonoid glycosides. Among them, 2-methyl-1,4,6-trihydroxy-anthraquinone is a new one, and three compounds were found for the first time in this genus. MTT assay resulted that the n-butanol extract and four isolated compounds inhibited the proliferation of chronic myelogenous leukaemia cells. The results from Hoechst 33343 staining and caspase 3-inducing exhibited that those four tested compounds induced apoptosis and activated caspase 3 (p < 0.05). One of them, isorhamnetin-3-O-ß-rutinoside showed the most activity with IC50 value of 394.68 ± 25.12 µM.

The impact of guest compounds on cyclodextrin aggregation behavior: A series of structurally related parabens.

Several studies have demonstrated the presence of aggregates in aqueous cyclodextrin containing solutions. The presence of guest compounds has been shown to influence this cyclodextrin aggregation process. In an attempt to gain insight into the effect of the physicochemical properties of the guest compound on 2-hydroxypropyl-ß-cyclodextrin aggregation formation, a series of structurally related parabens was selected as model compounds. Using nuclear magnetic resonance spectroscopy and phase solubility studies, these parabens, differing only in side chain length, were demonstrated to form inclusion complexes with 2-hydroxypropyl-ß-cyclodextrin. Additional techniques were subsequently applied to evaluate the aggregation behavior of this cyclodextrin in presence of the selected parabens. Solutions containing a broad range of 2-hydroxypropyl-ß-cyclodextrin concentrations were saturated with the guest compounds and were used as test media. Results obtained from dialysis experiments, dynamic light scattering and mass spectrometry revealed a positive effect of the side chain length of the parabens on aggregate formation: in presence of heptylparaben, more and larger aggregates were observed than in presence of parabens with shorter side chains such as methyl- and butylparaben. No clear connection could be demonstrated between the cyclodextrin concentration and the extent of aggregate formation in presence of the guest compound.

Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions.

Cyclodextrins (CDs) are enabling pharmaceutical excipients that can be found in numerous pharmaceutical products worldwide. Because of their favorable toxicologic profiles, CDs are often used in toxicologic and phase I assessments of new drug candidates. However, at relatively high concentrations, CDs can spontaneously self-assemble to form visible microparticles in aqueous mediums and formation of such visible particles may cause product rejections. Formation of subvisible CD aggregates are also known to affect analytical results during product development. How and why these CD aggregates form is largely unknown, and factors contributing to their formation are still not elucidated. The physiochemical properties of CDs are very different from simple amphiphiles and lipophilic molecules that are known to self-assemble and form aggregates in aqueous solutions but very similar to those of linear oligosaccharides. In general, negligible amounts of aggregates are formed in pure CD solutions, but the aggregate formation is greatly enhanced on inclusion complex formation, and the extent of aggregation increases with increasing CD concentration. The diameter of the aggregates formed is frequently less than about 300 nm, but visible aggregates can also be formed under certain conditions.

A new lignan glycoside from the aerial parts and cytotoxic investigation of Uvaria rufa.

Chemical investigation of the aerial parts of Uvaria rufa (Dunal) Blume collected from Vietnam yielded one new lignan glycoside, ufaside (1), along with six known compounds, oxoanolobine (2), ergosta-4,6,8(14),22-tetraen-3-one (3), catechin (4), epicatechin (5), daucosterol (6) and glutin-5-en-3-one (7). Their chemical structures were determined by using NMR, HR-MS spectroscopic analyses and in comparison with the reported data. A cytotoxic analysis of U. rufa herb extracts was performed for the first time using nine human cancer cell lines (MCF-7, MDA-MB-231, LNCaP, MKN7, SW480, KB, LU-1, HepG2 and HL-60) derived from different tumour types. Of these seven constituents, compounds 2 and 3 displayed moderate cytotoxicity against the human lung adenocarcinoma cell line (LU-1) with IC50 values of 9.22 ± 1.02 µg/mL and 10.21 ± 1.16 µg/mL, respectively.

Synthesis and biological evaluation of oseltamivir analogues from shikimic acid.

New oseltamivir analogues were designed and synthesized, starting from shikimic acid. Biological evaluation against three human cancer cell lines (KB, MCF7 and Lu-1) showed that many of them exhibited cytotoxic activity. Azides 5 are more active than the corresponding amines 6. Thus, the reduction of the azide group into amine led to the loss of cytotoxicity. The compounds with a cyclohexanemethyloxy group at C-3 were more active than the other investigated compounds belonging to the same series. This cyclohexanemethyloxy group seems to be critical for the cytotoxic activity of this class of compounds. The synthetic oseltamivir analogues 6a-e had no inhibition activity, even at the concentration of 50 microM when they were evaluated for their in vitro influenza A neuraminidase inhibitory activity by an enzymatic assay.

Toxicity and anticancer effects of an extract from Selaginella tamariscina on a mice model.

The toxicity and antitumour effect of the ethanol extract of Selaginella tamariscina (STE), a plant widely used in folk medicine, were examined in a mice model. In the single-dose acute toxicity test, an oral administration of 10,000 mg kg(-1) STE did not cause any lethality. The sub-acute toxicity study showed that the treatment by 250, 1000 and 3000 mg kg(-1 )day(-1) for 30 continuous days did neither alter the body weights nor the haematological parameters in BALB/c mice. The anticancer effect of STE was evaluated in BALB/c mice inoculated with Lewis lung carcinoma cells. Oral administration of STE could not prevent the tumour formation but provided strong inhibition of tumour growth.

In vivo anticancer activity of maesopsin 4-O-β-glucoside isolated from leaves of Artocarpus tonkinensis A. Chev. Ex Gagnep

OBJECTIVE@#To investigate the antitumor effect of maesopsin 4-O-β-glucoside (TAT2) isolated from the leaves of Artocarpus tonkinensis (A. tonkinensis) A. Chev. ex Gagnep.@*METHODS@#The antitumor activity of TAT2 was evaluated in Lewis lung carcinoma (LLC) tumor-bearing mice. BALB/c mice had tumors induced by implantation with 2 × 10(6) LLC cells into the subcutaneous right posterior flank. Tumor-bearing mice were treated orally with a range of doses of TAT2 and a standard drug, doxorubicin. Animals were observed for tumor growth and mortality rate. Blood was collected to determine hematological and biochemical parameters.@*RESULTS@#TAT2 was isolated from an ethanolic extract of A. tonkinensis leaves. Its structure was determined by MS and NMR spectroscopy, and identified as TAT2. The compound did not show acute toxicity at the highest dose tested (2000 mg/kg body weight). TAT2 exhibited antitumor activity by decreasing tumor growth, increasing the survival rate, and ameliorating some hematological and biochemical parameters at doses of 100 and 200 mg/kg body weight (P < 0.05).@*CONCLUSIONS@#These results indicate that TAT2 possesses clear antitumor activity. Due to its bioavailability and low toxicity, and the fact that it could be isolated in a large scale from A. tonkinensis leaves, the compound shows promise as a potential anticancer drug.

In vivo anticancer activity of maesopsin 4-O-β-glucoside isolated from leaves of Artocarpus tonkinensis A. Chev. Ex Gagnep

Objective: To investigate the antitumor effect of maesopsin 4-O-β-glucoside (TAT2) isolated from the leaves of Artocarpus tonkinensis (A. tonkinensis) A. Chev. ex Gagnep. Methods: The antitumor activity of TAT2 was evaluated in Lewis lung carcinoma (LLC) tumor-bearing mice. BALB/c mice had tumors induced by implantation with 2 × 10