Vichai Reutrakul

Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii

Triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii Hook f. (Celastraceae), has been shown to demonstrate potent antileukemic activity in rodent models at remarkably low treatment doses. A variety of other physiological responses are known to be mediated by this compound, including immunosuppressive and antifertility effects. We currently report that triptolide was not mutagenic toward Salmonella typhimurium strain TM677, either in the presence or absence of a metabolic activating system. Relatively potent but non-specific cytotoxicity was observed with a panel of cultured mammalian cell lines, and modest antitumor activity was observed when an i.p. dose of 25 microg was administered three times weekly to athymic mice carrying human breast tumors. Treatment regimens involving higher doses of triptolide (e.g. 50 microg/mouse three times weekly) were lethal.

Antitumor activity of triptolide against cholangiocarcinoma growth in vitro and in hamsters.

One of the diverse biological activities of triptolide, a diterpene from Tripterygium wilfordii, is its antitumor effect. We recently reported its in vitro cytotoxicity against several cultured tumor cell lines. Limited availability of purified fraction has prevented detailed investigation on its antitumor activity. In the present study, we showed by in vitro cytotoxicity assay and in vivo inhibition of tumor growth in hamsters that the triptolide was also highly effective against cholangiocarcinoma, a highly fatal tumor predominantly occurring in developing countries. Its ED50 for these hamster cholangiocarcinoma cell lines was found to be as low as 0.05 microg/ml. The compound was highly potent in the induction of apoptotic death in these tumor cells. DNA fragmentation and disintegrating apoptotic cells could be observed within 24 h of exposure to 0.5 microg/ml triptolide. The compound was tested against the growth of cholangiocarcinoma in a hamster model. A significant growth inhibition (P < 0.05) was noted in triptolide-treated hamsters (each of the 10 animals received 10 injections for a total of 1.2 mg/animal). At the time of sacrifice 1 month after the initial injection, the mean tumor mass of the treated group was only 20-25% of that of the control group.

Anti-inflammatory cyclohexenyl chalcone derivatives in Boesenbergia pandurata.

The cyclohexenyl chalcone derivative [(-)-hydroxypanduratin A], together with the previously known panduratin A, sakuranetin, pinostrobin, pinocembrin, and dihydro-5,6-dehydrokawain were isolated from the chloroform extract of the red rhizome variety of Boesenbergia pandurata (Robx.) Schltr. [currently known as Boesenbergia rotunda (L.) Mansf., Kulturpfl.]. Their structures were assigned on the basis of their spectroscopic data. (-)-Hydroxypanduratin A and (-)-panduratin A showed significant topical anti-inflammatory activity in the assay of TPA-induced ear edema in rats.

Anti-inflammatory and antipyretic properties of Clerodendrum petasites S. moore

The methanol extract from Clerodendrum petasites S. Moore (CP extract) was assessed for anti-inflammatory and antipyretic activities on the experimental animal models. It was found that CP extract possessed moderate inhibitory activity on acute phase of inflammation in a dose-related manner as seen in ethyl phenylpropiolate-induced ear edema (ED(50)=2.34 mg/ear) as well as carrageenin-induced hind paw edema (ED(30)=420.41 mg/kg) in rats. However, CP extract did not elicit any inhibitory effect on arachidonic acid-induced hind paw edema in rats. In subchronic inflammatory model, CP extract provoked a significant reduction of transudation but had no effect on proliferative phase when tested in cotton pellet-induced granuloma model. CP extract also reduced the alkaline phosphatase activity in serum of rats in this animal model. Moreover, CP extract possessed an excellent antipyretic effect when tested in yeast-induced hyperthermic rats. It is postulated that the anti-inflammatory and antipyretic effects of CP extract are caused by the inhibition of the prostaglandin synthesis. Anyhow, CP extract did not possess any analgesic activity in acetic acid-induced writhing response in mice. The results obtained show that C. petasites has beneficial properties since it possesses potent antipyretic and moderate anti-inflammatory activities without ulcerogenic effect.

Flavonoids in the black rhizomes of Boesenbergia panduta

Abstract 5-Hydroxy-7-methoxyflavanone, 5,7-dimethoxyflavanone, 5-hydroxy-7-methoxyflavone 5-hydroxy-7,4′-dimethoxyflavone, 5,7-dimethoxyfiavone, 5,7,4′-trimethoxyflavone, 5,7,3′,4′-tetramethoxyflavone, 5-hydroxy-3,7-dimethoxyflavone, 5-hydroxy-3,7,4′-trimethoxyflavone, 3,5,7-trimethoxyflavone and 5-hydroxy-3,7,3′,4′-tetramethoxyflavone have been isolated from the black rhizomes of Boesenbergia pandurata .

Novel cytotoxic 1H-cyclopenta[b]benzofuran lignans from Aglaia elliptica

Abstract Bioassay-guided fractionation of the stems and fruits of Aglaia elliptica using human oral epidermoid carcinoma (KB) cells, led to the isolation of five cyclopenta[b]benzofurans, constituted by methyl rocaglate (1) and four novel compounds (2–5), along with three known dammarane triterpenoids. Compound 5 possesses an unusual formyl ester substituent at the C-1 position. The structures of the novel compounds were established on the basis of spectroscopic methods. Compounds 1–5 were found to be very potent cytotoxic substances when evaluated against a panel of human cancer cell lines.

Evaluation of anti-HSV-2 activities of Barleria lupulina and Clinacanthus nutans.

Barleria lupulina Lindl. and Clinacanthus nutans (Burm. f.) Lindau, both belonging to the family Acantaceae, are well-known medicinal plants used in Thai folklore medicine. Virucidal effects of organic extracts of these two plants against herpes simplex virus type 2 strain G, HSV-2 (G), the standard HSV-2 strain were noted. The extracts were assessed for intracellular activities against HSV-2 (G) and five clinical HSV-2 isolates. B. lupulina extract exhibited activity against all five isolates but not the standard strain while that of C. nutans did not show any activity against these viruses as determined by plaque inhibition assay. When the activities were verified by yield reduction assay, anti-HSV-2 activities of B. lupulina extract were observed against HSV-2 (G) as well. The results suggest a therapeutic potential of B. lupulina but not C. nutans against HSV-2.

The anti-inflammatory effects and the inhibition of neutrophil responsiveness by Barleria lupulina and Clinacanthus nutans extracts

AIM OF THE STUDY To investigate the anti-inflammatory activities of Barleria lupulina Lindl and Clinacanthus nutans (Burm.f.) Lindau extracts using two neutrophil-dependent acute inflammatory models and, in order to elucidate underlying cellular mechanisms, the effects of the extracts on human neutrophil responsiveness was investigated. MATERIALS AND METHODS The in vivo inflammatory models examined were carrageenan-induced paw oedema and ethyl phenylpropiolate-induced ear oedema in rats. Myeloperoxidase (MPO) activity was assayed as an indicator of neutrophil migration. Human neutrophil functional responsiveness was determined by measuring fMLP-induced chemotaxis, superoxide anion generation (SAG), and release of MPO and elastase. Apoptosis was assessed morphologically and flow-cytometrically. Neutrophil viability was assessed by trypan blue exclusion and MTT cytotoxicity assays. RESULTS Both extracts induced powerful dose-dependent inhibitory effects in both edema models in rats. Importantly, there was a significant inhibition of MPO activity in the inflamed tissue indicating that the anti-inflammatory effect of the extracts is associated with reduced neutrophil migration. Although both extracts did not affect neutrophil viability or apoptosis, treatment of neutrophils with the extracts concentration-dependently inhibited fMLP-induced chemotaxis, SAG, and MPO and elastase release. CONCLUSIONS These findings suggest that the powerful anti-inflammatory properties of Barleria lupulina Lindl and Clinacanthus nutans (Burm.f.) Lindau extracts are mediated, in part, by inhibition of neutrophil responsiveness.Barleria lupulina Lindl, Clinacanthus nutans (Burm. f.)Lindau; Oedema formation; Neutrophil responsiveness.

Regioselective C2 Sulfonylation of Indoles Mediated by Molecular Iodine

A facile and general method for regioselective C2 sulfonylation reaction of indoles mediated by iodine is described. The 2-sulfonylated products were obtained up to 96% yield under mild reaction conditions (room temperature, 2 h).

Fluoride-Catalyzed Addition of PhSCF2SiMe3 to N-Substituted Cyclic Imides Followed by Radical Cyclization: General Synthetic Strategy of gem-Difluoromethylenated 1-Azabicyclic Compounds

PhSCF(2)SiMe(3) (1) was found, for the first time, to undergo fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reaction to cyclic imides 2, affording the corresponding adducts 3 in moderate to good yields. Reductive cleavage of the phenylsulfanyl group of N-alkylated adducts 3 with Bu(3)SnH/AIBN yielded gem-difluoromethylated products 4. Under the same reduction conditions, N-alkenylated and N-alkynylated adducts 3 afforded the corresponding gem-difluoromethylenated 1-azabicyclic compounds 5 and 6 with trans stereoselectivity. These compounds were employed as precursors for preparing substituted gem-difluoromethylenated pyrrolizidinones and indolizidinones 7 and 8 by treatment with Et(3)SiH/BF(3) x OEt(2), and compounds 9 and 10 by nucleophilic displacement of the hydroxyl group, using organosilanes in the presence of BF(3) x OEt(2). The synthesis of highly substituted gem-difluoromethylenated pyrrolizidines 13 and 14 was also demonstrated.