bruceoside-a and brusatol

Bruceoside A, an abundant quassinoid glycoside in Fructus Bruceae, was chosen for the pharmacokinetic study. It is the first case report on the pharmacokinetic study of quassinoid glycosides so far. A sensitive, accurate, and repeatable UHPLC-MS/MS method was developed for the determination of bruceoside A and its major metabolite. The results showed bruceoside A could be transformed into the potent anticancer component brusatol in vivo, rather than its direct deglycosylated metabolite bruceosin. And the intestinal bacteria were proposed to take a potential role during such transformation. Based on the present study, it could be concluded that the quassinoid glycosides possessing weak activities in vitro could do contribution to the anticancer properties of Fructus Bruceae in vivo via transforming into more active metabolites.

Topics: Animals; Antineoplastic Agents, Phytogenic; Brucea javanica; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Glycosides; Male; Mice; Mice, Inbred ICR; Quassins; Tandem Mass Spectrometry

In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Differentiation; Cell Division; Cell Membrane; DNA; Drug Screening Assays, Antitumor; Female; Glaucarubin; Glycosylation; HL-60 Cells; Humans; Inhibitory Concentration 50; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Models, Biological; Molecular Structure; Nitroblue Tetrazolium; Organ Culture Techniques; Plants, Medicinal; Quassins; Rats; Simaroubaceae; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured

Three active components were isolated from treated dry-fruits of Brucea javanica (L.) Merr by chromatographic methods, and they were identified as Brusatol (I), Bruceine D (II), Bruceosidae A (III) by means of UV, IR, 1H-NMR, 13C-NMR spectroscopic analysis methods.

Topics: Brucea; Magnetic Resonance Spectroscopy; Plants, Medicinal; Quassins; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

The quassinoids bruceantin, brucein D, brucein E, bruceoside A, and brusatol significantly inhibited P-388 lymphocytic leukemic cell RNA and protein synthesis in tissue culture. However, DNA synthesis inhibition seemed to correlate more directly with the anti-neoplastic activity of these compounds in the in vivo P-338 survival system. In vitro, brusatol and bruceoside A marginally inhibited 10-day P-388 lymphocytic leukemia DNA polymerase, RNA polymerase, thymidylate synthetase, dihydrofolate reductase, phosphoribosyl pyrophosphate aminotransferase, and cathepsin protease activities. In vivo studies demonstrated similar inhibition and elevated cyclic AMP levels, correlating positively with the antineoplastic activity of individual compounds. Purine synthesis was inhibited drastically by brusatol in vivo, and one key inhibition site in purine synthesis was at phosphoribosyl pyrophosphate aminotransferase, the regulatory enzyme. Histone phosphorylation and ribonucleotide reductase activity also were inhibited marginally by brusatol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cells, Cultured; DNA, Neoplasm; Glaucarubin; Leukemia, Experimental; Male; Mice; Mice, Inbred DBA; Pyrans; Quassins; RNA, Neoplasm