glaucarubin and brusatol

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

The C-15 senecioyl side chain of brusatol was interchanged with fluorinated acyl groups, and the C-3 hydroxy group of bruceolide was esterified with fluorinated acyl chlorides. These fluorinated quassinoids 11, 12, 13, and 17 showed significant cytotoxic activity against eight human cancer cell lines including small and non-small cell lung, colon, CNS, ovarian and renal cancers, leukemia, and melanoma with 17 being about 100 times more potent than 11, 12, and 13. The activity of 17 was similar to that of bruceantin (1) in this in vitro cell line panel.

Topics: Acylation; Antineoplastic Agents, Phytogenic; Fluorine; Glaucarubin; Humans; Models, Chemical; Quassins; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Proteins; Glaucarubin; In Vitro Techniques; Phenanthrenes; Protein Biosynthesis; Quassins; Rabbits; Reticulocytes

A series of quassinoids were observed to be potent inhibitors of induced inflammation and arthritis in rodents. Brusatol afforded the most potent activity followed by brucein-D. A 3-hydroxy-delta 3-2-oxo moiety in brusatol or a 1-hydroxy-delta 3-2-oxo moiety in brucein-D, as well as a C-15 ester-bearing delta-lactone ring in brusatol and C-11 and C-12 free hydroxyl groups are required in both quassinoids for potent anti-inflammatory activity. Preliminary studies indicate that one of the modes of action of quassinoids as anti-inflammatory agents is to stabilize lysosomal membranes, reducing the release of hydrolytic enzymes that cause damage to surrounding tissues.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Glaucarubin; Liver; Lysosomes; Male; Mice; Oxidative Phosphorylation; Phenanthrenes; Prostaglandin-Endoperoxide Synthases; Quassins; Rats; Rats, Inbred Strains; Structure-Activity Relationship

The mechanism by which brusatol inhibits protein synthesis in rabbit reticulocytes has been investigated. When added to reticulocyte lysates, brusatol inhibits endogenous protein synthesis only after a lag of 2-4 min at 30 degrees C. During this period 80 S ribosomes accumulate. Brusatol is equally effective in inhibiting endogenous protein synthesis in lysates and poly(U)-directed polyphenylalanine synthesis with runoff ribosomes. In fractionated reticulocyte systems, brusatol does not inhibit formation of the ternary, 40 S, and 80 S initiation complexes, but does inhibit the reaction of puromycin with initiation complexes containing [35S]Met-tRNAf. These data suggest that brusatol inhibits the peptidyl transferase elongation reaction of protein synthesis, but can do so only after one round of protein synthesis has been completed. Thus, the mechanism of action of brusatol in the rabbit reticulocyte system is very similar to the effects previously reported for bruceantin in a yeast system.

Topics: Animals; Blood Proteins; Glaucarubin; In Vitro Techniques; Peptide Chain Elongation, Translational; Peptide Chain Initiation, Translational; Peptidyl Transferases; Phenanthrenes; Quassins; Rabbits; Reticulocytes

Based on the fact that some known antineoplastic agents possess an ester moiety within their structure, the esters of helenalin, a sesquiterpene lactone, and of brusatol and bruceantin, quassinoids, were synthesized and tested for antileukemic activity in the P-388 screen. These agents gave different T/C% values dependent on the P-388 lymphocytic leukemia strain and the host strain of mice used. Later studies demonstrated that the agents caused different degrees of inhibition of nucleic acid and protein synthesis in the various P-388 strains. The higher the degree of inhibition of precursor incorporation into the nucleic acid or protein, the higher was the T/C% value obtained in a given P-388 strain. The study demonstrates the lack of consistency of P-388 lymphocytic leukemia cell lines used in various laboratories and indicates that the inbred strain of mice is a critical factor in the tolerance of drug toxicity and, thus, T/C% obtained.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cells, Cultured; DNA, Neoplasm; Glaucarubin; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred Strains; Neoplasm Proteins; Phenanthrenes; Quassins; Sesquiterpenes; Sesquiterpenes, Guaiane; Thymidine

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