Artepillin C was extracted from Brazilian propolis. Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) has a molecular weight of 300.40 and possesses antibacterial activity. When artepillin C was applied to human and murine malignant tumor cells in vitro and in vivo, artepillin C exhibited a cytotoxic effect and the growth of tumor cells was clearly inhibited. The artepillin C was found to cause significant damage to solid tumor and leukemic cells by the MTT assay, DNA synthesis assay, and morphological observation in vitro. When xenografts of human tumor cells were transplanted into nude mice, the cytotoxic effects of artepillin C were most noticeable in carcinoma and malignant melanoma. Apoptosis, abortive mitosis, and massive necrosis combined were identified by histological observation after intratumor injection of 500 microg of artepillin C three times a week. In addition to suppression of tumor growth, there was an increase in the ratio of CD4/CD8 T cells, and in the total number of helper T cells. These findings indicate that artepillin C activates the immune system, and possesses direct antitumor activity.
The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.
Synthesis of (-)-bevantolo1 hydrochloride from 3,4-dimethoxyphenethylamine and (S)-(+)-m-tolyl glycidyl ether derived from (R)-(-)-epichlorohydrin established the absolute configuration of the ( + ) and (-) enantiomer as R and S, respectively. The purity of the enantiomers was determines using a chiral cellulose column (CHIRALCEL OD@) which allowed drect separation of the enantiomers. A separation factor (a) of 4.20 and a resolution factor (Rs) of 9.21 were obtained. o 1995 Wiey-Liss, Inc.KEY WORDS: P-blockers, bevantolol, NC-1400, epichlorohydrin, absolute configuration, enantiomer, chiral cellulose column, dn-ect separationVarious p-adrenergic blocking agents (P-blockers), especially, l-amino-3-aryloxy-2-propanol derivatives, have been widely used for the treatment of cardiovascular disorders such as hypertension or angina pectoris. ' It has potent cardioselective P-blocking activity, and also possesses a-blocking and calcium blocking activities.3r4 These additional properties may be of advantage in the treatment of hypertension and may attenuate the disorders of P-blockers. In healthy subjects, it has been shown to cause a lowering effect on peripheral vascular resistance, and in patients with angina pectoris favorable effects on blood lipids have been reported.Most of the frequently prescribed p-blockers are supplied as racemates, but there are many reports suggesting differences in pharmacological and pharrnacodynamic andor pharmacokinetic properties between enantiomers of @-blockers. With respect to (+)-5, the differences in some pharmacological properties between enantiomers have already been reported. Furthermore, it is important to develop methods for determination of enantiomeric purity in order to investigate the metabolic pathways of (+)-5.In this paper, we report the absolute configuration of (-1-5, and describe a method for the direct column chromatographic separation of the enantiomers of (-+)-5. MATERIALS AND METHODSThe melting points were determined on a Yamato MP-21 and were uncorrected. The values of specific rotations were obtained on a JASCO DIP-360 digital polarimeter. 'H NMR 0 1995 Wiley-Liss, Inc.spectra were recorded on a JEOL JNM-EX400 NMR spectrometer with tetramethylsilane as the internal standard. Elemental analyses (C,H,N) were performed on a Heraus C,H,NRapid instrument. Optically active epichlorohydrins [(+)-or (-)-1 (over 98% ee)] were purchased from Daiso Co., Ltd. (Osaka, Japan). 3,4-Dimethoxyphenethyl~e (4) was purchased from Aldrich Japan Inc. (Tokyo, Japan) and Recordati Industria Chmica e Farmaceutica S.p. A. (Milano, Italy). High-Performance Liquid Chromatography (HPLC)The HPLC-system consisted of a JASCO BIP-1 HPCL pump and a JASCO UVIDEC-100-V W-spectrophotometer. The chiral analybcal columns contained CHIRALCEL OD@ (250 x 4.6 and 250 x 20 mi n; Daicel Chemical Industries, Ltd. (Osaka, Japan)). The mobile phase was composed of (1)
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A series of 2-(4-benzhydryl-1-piperazinyl)-1-phenylethanols (4) was synthesized and evaluated for calcium entry-blocking activity, assessed as inhibitory activity on calcium current in rat hippocampal pyramidal neurons by using a patch-clamp technique (10(-5) M), and cerebral vasodilating activity, assessed in terms of increase of vertebral blood flow after intravenous administration (1 mg/kg) in anesthetized dogs. Alkoxy substituents on the phenyl ring of the phenylethanol moiety conferred potent calcium entry-blocking activity and potent cerebral vasodilating activity. Among these compounds, 4i (NC-1100) was selected as the best analog. Some pharmacological properties of 4i are presented.
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