The hydroxide ion-catalyzed hydrolysis of securinine involves the ring opening of the lactone moiety. The rate of hydrolysis is insensitive to the ionic strength. The observed pseudo-first-order rate constants reveal a decrease of approximately 4-fold due to the increase in the MeCN content from 4 to 50% (v/v) in mixed aqueous solvent. The temperature dependence of the rate of hydrolysis follows the Eyring equation, which yields delta H* and delta S* as 11.0 kcal mol-1 and -34.5 cal deg-1 mol-1, respectively. The hydroxyl carboxylate product of the alkaline hydrolysis of securinine is shown to undergo cyclization in acidic medium to yield securinine. The observed pseudo-first-order rate constants for cyclization increase linearly with an increase in [H+]. The change in the content of MeCN from 3.8 to 47.2% (v/v) in mixed aqueous solvents does not show an effect on the rate of the cyclization reaction. The most plausible mechanisms for alkaline hydrolysis and acid cyclization reactions are also discussed.
Matched MeSH terms: Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds with 4 or More Rings
Leaf extracts of the Malaysian plant Aglaia laxiflora provided two cytotoxic compounds, a new rocaglaol rhamnoside (1), a known rocaglaol (2), new (but inactive) flavonol-cinnamaminopyrrolidine adducts (3-6), and their probable biosynthetic precursors (7 and trimethoxyflavonol). All structures were elucidated primarily by 2D NMR spectroscopy. The structure and stereochemistry of aglaxiflorin A (3) were confirmed by single-crystal X-ray crystallography.
A new carbazole alkaloid, 3-carbomethoxy-2-hydroxy-7-methoxycarbazole, Clausine-TY (1), together with two known carbazole alkaloid, Clausine-H (2) and Clausine-B (3), were isolated from the ethyl acetate extract of the stem bark of the Malaysian Clausena excavata. The structures of these compounds were elucidated by spectroscopic analyses. The new carbazole alkaloid shows significant cytotoxicity against CEM-SS cell line.
Consumption of probiotics has been associated with decreased risk of colon cancer and reported to have antimutagenic/ anti-carcinogenic properties. One possible mechanism for this effect involves physical binding of the mutagenic compounds, such as heterocyclic amines (HCAs), to the bacteria. Therefore, the objective of this study was to examine the binding capacity of bifidobacterial strains of human origin on mutagenic heterocyclic amines which are suspected to play a role in human cancers. In vitro binding of the mutagens Trp-p-2, IQ, MeIQx, 7,8DiMeIQx and PhIP by three bacterial strains in two media of different pH was analysed using high performance liquid chromatography. Bifidobacterium pseudocatenulatum G4 showed the highest decrease in the total HCAs content, followed by Bifidobacterium longum, and Escherichia coli. pH affects binding capacity; the highest binding was obtained at pH 6.8. Gram-positive tested strains were found to be consistently more effective than the gram-negative strain. There were significant decreases in the amount of HCAs in the presence of different cell concentrations of B. pseudocatenulatum G4; the highest decrease was detected at the concentration of 10(10) cfu/ml. The results showed that HCAs were able to bind with all bacterial strains tested in vitro, thus it may be possible to decrease their absorption by human intestine and increase their elimination via faeces.
The intake of heterocyclic amines is influenced by the amount and type of meat and fish ingested, frequency of consumption, cooking methods, cooking temperature, and duration of cooking. In this study, the dietary intake of heterocyclic amines in Malaysia and their main sources were investigated. Forty-two samples of meat and fish were analysed by high-performance liquid chromatography with photodiode array detector to determine the concentration of the six predominant heterocyclic amines, namely: 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f] quinoline(MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline (4,8-DiMeIQx), 2-amino-3,7,8-trimethylimidazo[4,5-f] quinoxaline (7,8-DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Dietary intake data were obtained using a food-frequency questionnaire when interviewing 600 Malaysian respondents. The level of total heterocyclic amines in food samples studies ranged from not detected to 38.7 ng g(-1). The average daily intake level of heterocyclic amine was 553.7 ng per capita day(-1). The intake of PhIP was the highest, followed by MeIQx and MeIQ. The results reveal that fried and grilled chicken were the major dietary source of heterocyclic amines in Malaysia. However, the heterocyclic amine intake by the Malaysian population was lower than those reported from other regions.
Hexacyclic derivatives share vital pharmacological properties, considered useful in Alzheimer's disease. The aim of this study was synthesis and its evaluation for acetyl cholinesterase inhibitory activity of novel hexacyclic analogues. Compound 4f, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.72 μmol/L.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/chemical synthesis*; Heterocyclic Compounds with 4 or More Rings/pharmacology; Heterocyclic Compounds with 4 or More Rings/chemistry
Six populations of Laurencia nangii were found to produce three bromoallenes; dihydroitomanallene B (1), itomanallene B (2) and pannosallene (3). Prior to this report, L. nangii were only known to produce C(15)-acetogenins with acetylene functionality. This could be regarded as a new chemical race of L. nangii. The compound structures were elucidated on the basis of spectroscopic analysis and comparison with those previously reported in literature. Compound 1, dihydroitomanallene B, was isolated as a new compound representing a minor variation of itomanallene B (2).
A new resveratrol dimer, acuminatol (1), was isolated along with five known compounds from the acetone extract of the stem bark of Shorea acuminata. Their structures and stereochemistry were determined by spectroscopic methods, which included the extensive use of 2D NMR techniques. All isolated compounds were evaluated for their antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (RSA) and the β-carotene-linoleic acid (BCLA) assays, and compared with those of the standards of ascorbic acid (AscA) and butylated hydroxytoluene (BHT). All compounds tested exhibited good to moderate antioxidant activity in the DPPH assay (IC₅₀s 0.84 to 10.06 mM) and displayed strong inhibition of β-carotene oxidation (IC₅₀s 0.10 to 0.22 mM). The isolated compounds were evaluated on the Vero cell line and were found to be non-cytotoxic with LC₅₀ values between 161 to 830 µM.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/isolation & purification*; Heterocyclic Compounds with 4 or More Rings/toxicity; Heterocyclic Compounds with 4 or More Rings/chemistry
The traditional use of Murraya koenigii as Asian folk medicine prompted us to investigate its wound healing ability. Three carbazole alkaloids (mahanine (1), mahanimbicine (2), mahanimbine (3)), essential oil and ethanol extract of Murraya koenigii were investigated for their efficacy in healing subcutaneous wounds. Topical application of the three alkaloids, essential oil and crude extract on 8 mm wounds created on the dorsal skin of rats was monitored for 18 days. Wound contraction rate and epithelialization duration were calculated, while wound granulation and collagen deposition were evaluated via histological method. Wound contraction rates were obvious by day 4 for the group treated with extract (19.25%) and the group treated with mahanimbicine (2) (12.60%), while complete epithelialization was achieved on day 18 for all treatment groups. Wounds treated with mahanimbicine (2) (88.54%) and extract of M. koenigii (91.78%) showed the highest rate of collagen deposition with well-organized collagen bands, formation of fibroblasts, hair follicle buds and with reduced inflammatory cells compared to wounds treated with mahanine (1), mahanimbine (3) and essential oil. The study revealed the potential of mahanimbicine (2) and crude extract of M. koenigii in facilitation and acceleration of wound healing.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/pharmacology; Heterocyclic Compounds with 4 or More Rings/chemistry
Eleven compounds:goniomicin A (1), goniomicin B (2), goniomicin C (3), goniomicin D (4), tapisoidin (5), goniothalamin (6), 9-deoxygoniopypyrone (7), pterodondiol (8), liriodenine (9), benzamide (10) and cinnamic acid (11), were isolated from the stem bark of Goniothalamus tapisoides. All compounds were identified by spectroscopic analysis and, for known compounds, by comparison with published data. Goniothalamin (6) exhibited mild cytotoxic activity towards a colon cancer cell line (HT-29), with an IC(50)value of 64.17 ± 5.60 µM. Goniomicin B (2) give the highest antioxidant activity in the DPPH assay among all compounds tested, with an IC(50) of 0.207 µM.
An investigation of the chemical constituents in Artocarpus obtusus species led to the isolation of three new xanthones, pyranocycloartobiloxanthone A (1), dihydroartoindonesianin C (2), and pyranocycloartobiloxanthone B (3). The compounds were subjected to antiproliferative assay against human promyelocytic leukemia (HL60), human chronic myeloid leukemia (K562), and human estrogen receptor (ER+) positive breast cancer (MCF7) cell lines. Pyranocycloartobiloxanthone A (1) consistently showed strong cytotoxic activity against the three cell lines compared to the other two with IC(50) values of 0.5, 2.0 and 5.0 μg/mL, respectively. Compound (1) was also observed to exert antiproliferative activity and apoptotic promoter towards HL60 and MCF7 cell lines at respective IC(50) values. The compound (1) was not toxic towards normal cell lines human nontumorigenic breast cell line (MCF10A) and human peripheral blood mononuclear cells (PBMCs) with IC(50) values of more than 30 μg/mL.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/isolation & purification; Heterocyclic Compounds with 4 or More Rings/pharmacology*; Heterocyclic Compounds with 4 or More Rings/chemistry
This study was set to investigate antiproliferative potential of dentatin (a natural coumarin isolated from Clausena excavata Burm. F) against prostate cancer and to delineate the underlying mechanism of action. Treatment with dentatin dose-dependently inhibited cell growth of PC-3 and LNCaP prostate cancer cell lines, whereas it showed less cytotoxic effects on normal prostate epithelial cell line (RWPE-1). The inhibitory effect of dentatin on prostate cancer cell growth was due to induction of apoptosis as evidenced by Annexin V staining and cell shrinkage. We found that dentatin-mediated accumulation of reactive oxygen species (ROS) and downregulated expression levels of antiapoptotic molecules (Bcl-2, Bcl-xL, and Survivin), leading to disruption of mitochondrial membrane potential (MMP), cell membrane permeability, and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-9, -3/7 activities, and subsequent DNA fragmentation. In addition, we found that dentatin inhibited TNF-α-induced nuclear translocation of p65, suggesting dentatin as a potential NF-κB inhibitor. Thus, we suggest that dentatin may have therapeutic value in prostate cancer treatment worthy of further development.
A new dibenzotetraaza[14]annulene bearing two 3,3-dimethylindolenine fragments at the meso positions (LH(2)), has been synthesized through a nontemplate method. X-ray crystallography shows that the whole molecule is planar. The basicity of the indolenine ring permits the macrocycle to be protonated external to the core and form LH(4)(2+)·2Cl(-). Yet another structural modification having strong C-H···π interactions was found in the chloroform solvate of LH(2). The latter two modifications are accompanied by a degree of nonplanar distortion. The antiaromatic core of the macrocycle can accommodate a number of metal ions, Mn(III), Fe(III), Co(II), Ni(II) and Cu(II), to form complexes of [Mn(L)Br], [Mn(L)Cl], [Fe(LH(2))Cl(2)](+)·Cl(-), [Co(L)], [Ni(L)], and [Cu(L)]. In addition, the reaction of LH(2) with the larger Pd(II) ion leads to the formation of [Pd(2)(LH(2))(2)(OAc)(4)] wherein the macrocycle acts as a semiflexible ditopic ligand to coordinate pairs of metal ions via its indolenine N atoms into dinuclear metallocycles. The compounds LH(2), [Co(L)], and [Ni(L)] are isostructural and feature close π-stacking as well as linear chain arrangements in the case of the metal complexes. Variable temperature magnetic susceptibility measurements showed thermally induced paramagnetism in [Ni(L)].
Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/chemistry
Goniothalamus macrophyllus (Blume) Hook. f. & Thoms. is a plant widely distributed in Malaysia. The aim of this study is to identify compounds from the roots of G. macrophyllus. The ground roots were extracted with aqueous methanol and partitioned sequentially with n-hexane, chloroform and butanol. Purification from this extracts afforded six compounds with two new compounds, namely goniolandrene-A (1), -B (2). The absolute configuration of goniolandrene B (2) was established by circular dichrosim. The compounds were cytotoxic against the P388 cells with IC50 values ranging from 0.42 to 160 μM. Goniothalamin (3) exhibited the highest inhibition of 0.42 μM.
A chemical investigation of the alkaloidal fraction of Dysoxylum acutangulum leaves led to the isolation and characterization of two new chromone alkaloid analogs named chrotacumines E and F (1 and 2, resp.). Structure elucidation of 1 and 2 was achieved by spectroscopic analyses, including 2D-NMR. Both of these alkaloids exhibited modest activities as tyrosinase inhibitors with 29.2 and 25.8% inhibition at 100 μg/ml, respectively.
Matched MeSH terms: Heterocyclic Compounds with 4 or More Rings/isolation & purification; Heterocyclic Compounds with 4 or More Rings/metabolism; Heterocyclic Compounds with 4 or More Rings/chemistry*
An alkaloid from Maclurodendron porteri has been isolated and characterized. Extraction process was conducted by acid-base extraction method followed by column chromatography. The structure was established by nuclear magnetic resonance spectroscopy and mass spectrometry. The compound was identified as haplophytin B which occurs commonly in the Rutaceae family. However, this is the first time this alkaloid was isolated and reported from the species. The compound showed no inhibition against Staphylococus aureus, Pseudomonas aeruginosa, Bacillus cereus and Escherichia coli and no cytotoxic activity against H199 and A549 cell lines.
Sunlight causes skin cancer by directly damaging DNA as well as by suppressing antitumor immune responses. A major mechanism whereby sunlight exerts immunosuppressive effects is by modulating the migration of chemokine (C-X-C motif) receptor 4 (CXCR4)-expressing dermal mast cells into and away from the skin. We have demonstrated the importance of this by showing that the systemic administration of the CXCR4 antagonist AMD3100 prevents sunlight-induced immunosuppression as well as the consequent carcinogenic response. Our results highlight the therapeutic potential of antagonizing CXCR4 signaling, especially in individuals who are at high risk of developing skin cancer.
One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.