Chemistry

Background Leptospirosis, one of the most widespread zoonotic infectious diseases worldwide, is caused by spirochetes bacteria of the genus Leptospira. The present study examined inhibitory activity of purified xanthones and crude extracts from Garcinia mangostana against both non-pathogenic and pathogenic leptospira. Synergy between γ-mangostin and penicillin G against leptospires was also determined. Methods Minimal inhibitory concentrations (MIC) of crude extracts and purified xanthones from G. mangostana and penicillin G for a non-pathogenic (L. biflexa serovar Patoc) and pathogenic (L. interrogans serovar Bataviae, Autumnalis, Javanica and Saigon) leptospires were determined by using broth microdilution method and alamar blue. The synergy was evaluated by calculating the fractional inhibitory concentration (FIC) index. Results The results of broth microdilution test demonstrated that the crude extract and purified xanthones from mangosteen possessed antileptospiral activities. ...

A new series of mangostin analogs of natural α-mangostin from mangosteen was prepared and their antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H 37 Ra. The results showed that the monoalkyl tetrahydro α-mangostin analogs displayed increased antimycobacterial activity as compared with the lead natural xanthone, α-mangostin. Among the tested compounds, 6-methoxytetrahydro α-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentration (MIC) of 0.78 µg/mL. The activity of the monoalkylated and monoacylated tetrahydro α-mangostins decreases as the length of carbon chain increases. The methyl ether analog was also active against the multidrug-resistant (MDR) strains with pronounced MICs of 0.78-1.56 µg/mL.

Three new prenylated xanthones, mangostenones C (1), D (2), and E (3), together with 16 known xanthones 4-19, were isolated from the young fruit (7-week maturity stage) of Garcinia mangostana. The structural elucidation of the new compounds was mainly established on the basis of 1D and 2D NMR and HR-MS spectroscopic analysis. Compound 1 showed cytotoxic properties against three human cancer cell lines, epidermoid carcinoma of the mouth (KB), breast cancer (BC-1), and small cell lung cancer (NCI-H187), with IC 50 values of 2.8, 3.53, and 3.72 m mg/ml, respectively. Among the isolates, a a-mangostin (12), the major metabolite, exhibited the most potent effects against the BC-1 cells with an IC 50 value of 0.92 m mg/ml, an activity greater than that of the standard drug ellipticine (IC 50 ‫64.1؍‬ m mg/ml). Compound 12 also showed the highest activity against KB cells, while gartanin (10) displayed the strongest activity against the NCI-H187 cells at the respective IC 50 values of 2.08 m mg/ml and 1.08 m mg/ml.

Information about the anti-inflammatory activity and metabolism of-mangostin (-MG), the most abundant xanthone in mangosteen fruit, in human cells is limited. On the basis of available literature, we hypothesized that-MG will inhibit the secretion of pro-inflammatory mediators by control and activated macrophage-like THP-1, hepatic HepG2, enterocyte-like Caco-2, and colon HT-29 human cell lines, as well as primary human monocyte-derived macrophages (MDM), and that such activity would be influenced by the extent of metabolism of the xanthone.-MG attenuated TNF-and IL-8 secretion by the various cell lines but increased TNF-output by both quiescent and LPS-treated MDM. The relative amounts of free and phase II metabolites of-MG and other xanthones present in media 24 h after addition of-MG was shown to vary by cell type and inflammatory insult. Increased transport of xanthones and their metabolites across Caco-2 cell monolayers suggests enhanced absorption during an inflammatory episode. The anti-inflammatory activities of xanthones and their metabolites in different tissues merit consideration.

aand c-Mangostin are the most abundant prenylated xanthones present in the fruit of the mangosteen tree. These compounds have been reported to possess numerous bioactivities that have provided the impetus for use of mangosteen products as nutraceuticals and in functional foods and dietary supplements. The health-promoting benefits of mangosteen are dependent on delivery of the xanthones to target tissues. Here, we used simulated digestion and Caco-2 cells to investigate the digestive stability, bioaccessibility, and intestinal cell transport of aand cmangostin. Recovery of aand c-mangostin after simulated digestion of pericarp and fruit pulp exceeded 90%. Transfer of aand c-mangostin to the aqueous fraction during simulated digestion was efficient (65-74%) and dependent on bile salts suggesting that micellarization is required for optimal bioaccessibility of xanthones. Cell uptake of xanthones from micelles was dose dependent and intracellular concentrations were maximum by 1 h. Both free and phase II metabolites of a-mangostin were transported in the basolateral compartment and metabolites also effluxed into the apical chamber. Transepithelial transport of a-mangostin was increased during prandial-like compared to fasted conditions suggesting that absorption is enhanced by dietary fat.

A new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line is examined to determine the relationship between the structural properties and the biological activity of these compounds-the 3-D quantitative structure-activity relationship (3D-QSAR)-using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best CoMFA and CoM-SIA models were obtained using the atom-based alignment of 33 compounds, 22 training compounds and 11 tested compounds, and these give desirable statistics; those for the CoMFA standard model were: r cv 2 = 0.691, r 2 = 0.998, S press = 0.178, s = 0.014 and F = 1080.765, while CoM-SIA combined steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields: r cv 2 = 0.600, r 2 = 0.988, S press = 0.206, s = 0.034 and F = 284.433. The 3D-QSAR models calculated satisfactory test set activities. The 3D-QSAR contour plots correlated strongly with the experimental data for the binding topology. For this reason, these results would be beneficial for predicting affinities with the compounds of interest, and they are advantageous for guiding the design and synthesis of new and more effective anticancer agents. Keywords CoMFA Á CoMSIA Á Xanthone derivatives Á Oral human epidermoid carcinoma (KB) cancer cell line

AIM: To investigate the effect of α-mangostin on the growth and apoptosis induction of human colon cancer cells. METHODS: The three colorectal adenocarcinoma cell lines tested (COLO 205, MIP-101 and SW 620) were treated with α-mangostin to determine the effect on cell proliferation by MTT assay, cell morphology, chromatin condensation, cell cycle analysis, DNA fragmentation, phosphatidylserine exposure and changing of mitochondrial membrane potential. The molecular mechanisms of α-mangostin mediated apoptosis were further investigated by Western blotting analysis including activation of caspase cascade, cytochrome c release, Bax, Bid, p53 and Bcl-2 modifying factor. RESULTS: The highest inhibitory effect of α-mangostin on cell proliferation of COLO 205, MIP-101 and SW 620 were 9.74 ± 0.85 μg/mL, 11.35 ± 1.12 μg/mL and 19.6 ± 1.53 μg/mL, respectively. Further study showed that α-mangostin induced apoptotic cell death in COLO 205 cells as indicated by membrane blebbing, chromatin condensation, DNA fragmentation, cell cycle analysis, sub-G1 peak (P < 0.05) and phosphatidylserine exposure. The executioner caspase, caspase-3, the initiator caspase, caspase-8, and caspase-9 were expressed upon treatment with α-mangostin. Further studies of apoptotic proteins were determined by Western blotting analysis showing increased mitochondrial cytochrome c release, Bax, p53 and Bmf as well as reduced mitochondrial membrane potential (P < 0.05). In addition, up-regulation of tBid and Fas were evident upon treatment with α-mangostin (P < 0.01). CONCLUSION: α-Mangostin may be effective as an anti-cancer agent that induced apoptotic cell death in COLO 205 via a link between extrinsic and intrinsic pathways.

Previous investigation showed that polyphenols abundantly found in many plants could inhibit Cl − secretion. The present study was aimed to investigate the effect of phenol containing xanthone derivatives on cAMP-activated intestinal Cl − secretion and evaluate potential benefits of these compounds in the treatment of cholera. Main methods: Four hydroxy xanthones were synthesized via oxidative coupling reaction of the corresponding ortho-hydroxybenzoic acids and hydroxyphenols. Short-circuit current and apical Cl − current measurements across monolayers of human intestinal epithelial (T84) cell and Fisher rat thyroid cells transfected with human CFTR (FRT-hCFTR cell) were performed to determine the effect of hydroxyxanthones on cAMP-activated Cl − secretion. Intracellular cAMP was measured by immunoassay methods. Anti-diarrheal efficacy was evaluated using closed loop model of cholera. Key findings: Among the tested xanthones, 1,3,6-trihydroxyxanthone (THX-001) was found to be the most potent derivative in the inhibition of cAMP-activated Cl − secretion across T84 cell monolayers (IC 50~1 00 μM). Electrophysiological analysis of T84 cells and FRT-hCFTR cells revealed that THX-001 targeted two distinct cAMP-activated Cl − channels in the apical membrane of T84 cells, namely, CFTR and inward rectifying Cl − channel (IRC). In contrast, THX-001 had no effect on intracellular cAMP levels in these cells. Importantly, THX-001 completely abolished cholera toxin-induced Cl − secretion across T84 cell monolayers and significantly inhibited cholera toxin-induced intestinal fluid secretion in mouse closed loop models. Significance: This study revealed that hydroxyxanthone represents another chemical class of polyphenolic compounds that may hold promise as anti-secretory therapy for cholera.

The present study examined effects of alpha-mangostin (α-MG) supplementation on the retinal microvasculature, including ocular blood flow (OBF) and blood-retinal barrier (BRB) permeability in a type 2 diabetic animal model. Male Sprague-Dawley rats were divided into four groups: normal control and diabetes with or withoutα-MG supplementation. Alpha-mangostin (200 mg/Kg/day) was administered by gavage feeding for 8 weeks. The effects ofα-MG on biochemical and physiological parameters including mean arterial pressure (MAP), OBF, and BRB leakage were investigated. Additionally, levels of retinal malondialdehyde (MDA), advance glycation end products (AGEs), receptor of advance glycation end products (RAGE), tumour necrosis factor alpha (TNF-α), and vascular endothelial growth factor (VEGF) were evaluated. The elevated blood glucose, HbA1c, cholesterol, triglyceride, serum insulin, and HOMA-IR were observed in DM2 rats. Moreover, DM2 rats had significantly decreased OBF but statistically...

Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that nonindoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of nonindoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; the 5,7-dimethyl-2-aryl-3Hpyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3Hpyrrolizin-3-ones represent a new class of angiogenesis inhibitors.

Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen. Synthetic Communications: an international journal for rapid communication of synthetic organic chemistry, 47 (1), 62-67. Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen Abstract 2-Aryl isatogens and their 3-imino derivatives have been extensively studied but to date there have been no reported variants carrying pyrrolyl substituents at the 2-position. This study describes the unexpected synthesis of two novel 3-imino-2-(pyrrol-2-yl) isatogen derivatives upon attempted amide couplings with (E)or (Z)-3-(3,5-dimethyl-1H-pyrrol-2-yl)-2-(2-nitrophenyl)acrylic acids and p-phenylenediamines in the presence of uronium-based coupling reagents. Imine hydrolysis of one derivative under mild acid conditions afforded a 2-pyrrolyl isatogen in high yield. The compound showed potent in vitro antiplasmodial activity against Plasmodium falciparum.

A new iridoid, pedunculariside, together with the known iridoid agnuside were isolated from the butanol extract of Vitex peduncularis stem bark. Both pedunculariside and agnuside showed preferential inhibition of COX-2, with IC 50 values of 0.15 ± 0.21 mg/ml and 0.026 ± 0.015 mg/ml respectively, while having only small inhibitory effects on COX-1. Both compounds did not exhibit cytotoxicity against vero cells.

The anti-alzheimer property against enzyme acetylcholinesterase of Thai medicinal plant Ventilago denticulata extracts and its chemical constituents was investigated. Isolation and purification of V. denticulata roots extracts afforded seven known quinone compounds: ventiloquinone I (1), 2–hydroxyislandicin (2), chrysophanol (3), physcion (4), emodin (5), questin (6) and ventilatone A (7) along with a large quantity of a mixture of common plant sterol, long chain fatty acids and tannin. The structures of quinones were assigned from combination of spectral data analysis especially 1D– and 2D NMR technique, and by comparison with the reported data. Compounds 2 and 4 were isolated for the first time from V. denticulata and from the genus Ventilago, respectively. The crude EtOAc extract (IC50 9.3±0.0001 μg/mL) revealed about 4 times more potent anti–AChE ability than that of the MeOH soluble fraction (IC50 36.3±0.0003 μg/mL), and only compound 7 exhibited effective inhibitory activity a...

Prenylated xanthones, isolated from the fruit hulls and the edible arils and seeds of Garcinia mangostana, were tested for their antituberculosis potential. a aand b b-Mangostins and garcinone B exhibited strong inhibitory effect against Mycobacterium tuberculosis with the minimum inhibitory concentration (MIC) value of 6.25 m mg/ml. Tri-and tetra-oxygenated xanthones with di-C 5 units or with a C 5 and a modified C 5 groups are essential for high activities. Substitution in the A and C rings has been shown to modify the bioactivity of the compounds.

The pericarp of mangosteen (Garcinia mangostana L.) is rich in various xanthones that are known to possess unique biological activities. In this work, we characterized the antiproliferative and cytotoxic activities of mangosteen xanthones both in vitro and in mice. In vitro analysis with a human colorectal adenocarcinoma cell line, COLO 205, showed that mangosteen xanthones not only inhibit the proliferation of target cells but also induce their death by apoptosis that involves the activation of the caspase cascade. In vivo analysis using a mouse subcutaneous tumor model with COLO 205 cells showed that, at relatively low doses, the growth of tumors was repressed upon intratumoral administration of mangosteen xanthones. When a higher dose of mangosteen xanthones was administered, the size of tumors was reduced gradually, and, in some mice, the disappearance of tumors was seen. Histopathological evaluation and biochemical analysis of tumors that received mangosteen xanthones indicate the induction of apoptosis in tumors, which resulted in the repression of their growth and the reduction of their sizes. These results demonstrate the potential of mangosteen xanthones to serve as anti-cancer agents for the chemotherapy of cancer.

The chloroform extract of the aerial part of Limnophila geoffrayi showed antimycobacterial and antioxidant activities. Bioassay-guided fractionation has led to the isolation of the flavones nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone, 1) and isothymusin (6,7dimethoxy-5,8,4'-trihydroxyflavone, 2). Both compounds 1 and 2 exhibited inhibition activity against Mycobacterium tuberculosis, with equal MIC value of 200 pg/mL. Only compound 2 exhibited antioxidant activity against the radical scavenging ability of DPPH, with the ICs0 value of 7.7 pg/mL. The crude hexane, chloroform and methanol extracts as well as the pure compounds 1 and 2 did not exhibit mutagenic activity in the Bacillus subtilis recassay.

The genus Artocarpus belongs to the Moraceae family, consisting of about 47 species distributed in southeastern Asia and the Pacific, and some species are cultivated throughout the tropics. 1) A number of Artocarpus species, including A. rigidus BLUME subsp. rigidus are found wild in the southern part of Thailand. No phytochemical investigation of this plant species has been reported to date. It should be noted that this plant species is different from A. rigida, the latter of which has been extensively investigated. 2-8) As part of an ongoing project on bioactive compounds from Thai plants for the treatment of tropical diseases, the plant species was investigated and it was found that the CHCl 3 and MeOH extracts exhibited antiplasmodial and antimycobacterial activities. Both crude extracts also showed cytotoxic activity against human epidermoid carcinoma of the nasopharynx (KB), human breast cancer (BC), and human small cell lung cancer (NCI-H187) cells. The present report deals with the isolation and antiplasmodial, antimycobacterial, and cytotoxic activities of the isolated new compounds 1 and 2, and the known compounds 3-6. Investigation of the chemical constituents of the root bark of A. rigidus subsp. rigidus resulted in the isolation of six compounds. These included two new phenolics with modified skeletons, the flavonoid 7-demethylartonol E (1) and the chromone artorigidusin (2), together with four, known, structurally modified phenolics, the xanthone artonol B (3), the flavonoid artonin F (4), the flavonoid cycloartobiloxanthone (5), and the xanthone artoindonesianin C (6). Compounds 3 and 4 were identified as artonol B and artonin F isolated previously from A. communis on the basis of spectroscopic (1 Hand 13 C-NMR spectral) comparisons. 9,10) On the same basis, compounds 5 and 6 were identified as cycloartobiloxanthone and artoindonesianin C isolated from A. nobilis 11) and A. teysmanii 12) respectively. Compound 1 was obtained as a pale brownish yellow powder , mp 224-226°C. The IR spectrum showed absorptions for the hydroxyl (3535, 3434 cm Ϫ1) and conjugated keto (1662 cm Ϫ1) groups. The HR-FAB-MS (positive ion mode) gave an [MϩH] ϩ ion at m/z 435.1446, corresponding to a molecular formula of C 25 H 22 O 7. The 1 H-NMR spectrum of 1 (Table 1) revealed two doublets (Jϭ1.9 Hz) at d 6.24 and 6.56 corresponding, respectively, to the characteristic H-6 and H-8 signals of a flavonoid. The 5,7-dihydroxyl substituted pattern was confirmed by HMBC correlations as shown