Epothilones A and B, natural products with minimal structural analogy to taxoids, have effects similar those of paclitaxel (Taxol®) in cultured cells on microtubule protein, but differ from retaining activity multidrug-resistant cells. We examined interactions the epothilones purified tubulin additional cell lines, including a paclitaxel-resistant ovarian carcinoma line an altered β-tubulin. The epothilones, like paclitaxel, induced form microtubules at low temperatures without GTP and/or...

Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, and combretastatin A-2 (CS-A2), 3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are structurally simple natural products isolated from the South African tree Combretum caffrum. They inhibit mitosis microtubule assembly competitive inhibitors of binding colchicine to tubulin [Lin et al. (1988) Mol. Pharmacol. 34, 200-208]. In contrast colchicine, drug effects on were not enhanced by...

A metabolite of estradiol, 2-methoxyestradiol (2ME), inhibits angiogenesis in the chicken embryo chorioallantoic membrane assay. Since 2ME causes mitotic perturbations, we examined its interactions with tubulin. In our standard 1.0 M glutamate system (plus mM MgCl2 at 37 degrees C), superstoichiometric concentrations (relative to tubulin) inhibited nucleation and propagation phases tubulin assembly but did not affect reaction extent. Although polymer formed presence was more cold-stable than...

As part of our continuing search for potential anticancer candidates among 2-phenyl-4-quinolones and 2-phenyl-4-quinazolinones, two series 6,7,2',3',4',5'-substituted 2-phenyl-4-quinazolinones 6,2',3',4',5'-substituted 2,3-dihydro-2-phenyl-4-quinazolinones were synthesized evaluated cytotoxicity as inhibitors tubulin polymerization. In general, a good correlation was found between the activities. Five 6-substituted heterocyclic 2-phenyl-4-quinozolinones (37-51) showed significant against...

The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, have been investigated. Subsequently we isolated series closely related bibenzyls, stilbenes, phenanthrenes from C. caffrum. Some the stilbenes proved be potent antimitotic agents which inhibited both tubulin polymerization binding colchicine tubulin. Combretastatin A-4 has shown most cancer cell growth inhibitor series. Presently this cis-stilbene is...

Computer-assisted structure analysis indicated (+)-discodermolide, a polyhydroxylated alkatetraene lactone marine natural product, was an antimitotic compound, and we confirmed this prediction. Previous work had shown accumulation of discodermolide-treated cells in the G2/M portion cell cycle, have now found that discodermolide arrests Burkitt lymphoma mitosis. Discodermolide-treated breast carcinoma displayed spectacular rearrangement microtubule cytoskeleton, including extensive bundling....

Data generated in the new National Cancer Institute drug evaluation program, which is based on inhibition of cell growth 60 human tumor lines, were used to compare compounds with agents known mechanism action terms their differential cytotoxicity. Two marine natural products, halichondrin B and homohalichondrin B, appeared repeatedly when data base was probed antimitotic agents. We confirmed that both highly cytotoxic (IC50 values for L1210 murine leukemia cells 0.3 1 nM, respectively),...

Abstract Escherichia coli ribosomes were made deficient in a 50 S ribosomal protein component by treatment with ethanol and NH4Cl their ability to carry out number of partial reactions involved polypeptide synthesis was examined. The found be competent all which the ribosome alone participated, but markedly involving an interaction ribosome, GTP, either supernatant factors T G. Nonenzymatic phenylalanyl-tRNA N-acetylphenylalanyl-tRNA binding peptidyl transferase activity essentially intact...

Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors MCF-7 cell growth. ATIs bearing 3-(3,4,5-trimethoxyphenyl)thio potent polymerization with IC(50)s in 2.0 (35) to 4.5 (37) microM range. They also inhibited growth nanomolar concentrations. The 3,4,5-trimethoxy substituted showed potencies comparable those reference compounds colchicine and combretastatin...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure of Curacin A, a Novel Antimitotic, Antiproliferative and Brine Shrimp Toxic Natural Product from the Marine Cyanobacterium Lyngbya majusculaWilliam H. Gerwick, Philip J. Proteau, Dale G. Nagle, Ernest Hamel, Andrei Blokhin, Doris L. SlateCite this: Org. Chem. 1994, 59, 6, 1243–1245Publication Date (Print):March 1, 1994Publication History Published online1 May 2002Published inissue 1 March...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation, Structure, and Synthesis of Combretastatins A-1 B-1, Potent New Inhibitors Microtubule Assembly, Derived from Combretum caffrumGeorge R. Pettit, Sheo Bux Singh, Margaret L. Niven, Ernest Hamel, Jean M. SchmidtCite this: J. Nat. Prod. 1987, 50, 1, 119–131Publication Date (Print):January 1987Publication History Published online1 July 2004Published inissue 1 January...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and evaluation of stilbene dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerizationMark Cushman, Dhanapalan Nagarathnam, D. Gopal, Asit K. Chakraborti, Chii M. Lin, Ernest HamelCite this: J. Med. Chem. 1991, 34, 8, 2579–2588Publication Date (Print):August 1, 1991Publication History Published online1 May 2002Published inissue 1 August...

Modulating the structure and function of tubulin microtubules is an important route to anticancer therapeutics, therefore, small molecules that bind cause mitotic arrest are immense interest. A large number synthetic natural compounds with diverse structures have been shown at colchicine site, one major binding sites on tubulin, inhibit assembly. Using recently determined X-ray tubulin:colchicinoid complex as template, we employed docking studies determine modes a set structurally site...

Dolastatin 10, a potent antimitotic peptide from marine animal, strongly inhibits microtubule assembly, tubulin-dependent GTP hydrolysis, and the binding of vinca alkaloids to tubulin. In studies [3H]vincristine protein, with vinblastine as control for competitive inhibition (Ki, 6.6 microM), we found that macrolide agents maytansine rhizoxin were also inhibitors (Ki values, 3.1 12 microM). 10 an unrelated antimitotic, phomopsin A, more but noncompetitive 1.4 2.8 Since and, much lesser...

Originally purified as a major lipid component of strain the cyanobacterium <i>Lyngbya majuscula</i> isolated in Curaçao, curacin A is potent inhibitor cell growth and mitosis, binding rapidly tightly at colchicine site tubulin. Because its molecular structure differs so greatly from that other inhibitors, we prepared series analogs to determine important structural features molecule. These modifications include reduction and<i>E</i>-to-<i>Z</i> transitions olefinic bonds 14-carbon side...

Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number analogs have now been synthesized or obtained C. caffrum. These vary in substituents on phenyl bridge carbons, length, unsaturation (i.e., stilbene derivatives, with...

Several arylthioindoles had excellent activity as inhibitors both of tubulin polymerization and the growth MCF-7 human breast carcinoma cells. Methyl 3-[(3,4,5-trimethoxyphenyl)thio]-5-methoxy-1H-indole-2-carboxylate (21), most potent derivative, showed IC50 = 2.0 μM, 1.6 times more active than colchicine about combretastatin A-4 (CSA4). Compound 21 inhibited cells at 13 nM. Colchicine CSA4 nM 17 values, respectively, with these

A novel series of 2-styrylquinazolin-4(3H-ones which inhibited tubulin polymerization and the growth L1210 murine leukemia cells was discovered. Extensive structure-activity relationship studies suggest that entire quinazolinone structure required, but activity further enhanced by halide or small hydrophobic substituents at position 6. These analogues did not substantially interfere with binding radiolabeled colchicine, vinblastine, GTP to weakly stimulated hydrolysis uncoupled from...

The lactone-bearing polyhydroxylated alkatetraene (+)-discodermolide, which was isolated from the sponge Discodermia dissoluta, induces polymerization of purified tubulin with and without microtubule-associated proteins or GTP, polymers formed are stable to cold calcium. These effects similar those paclitaxel (Taxol), but discodermolide is more potent. We confirmed that these properties represent hypernucleation phenomena; we obtained lower critical concentrations shorter than under a...

Laulimalide is a cytotoxic natural product that stabilizes microtubules. The compound enhances tubulin assembly, and laulimalide quantitatively comparable to paclitaxel in its effects on the reaction. also active P-glycoprotein overexpressing cells, while isolaulimalide, congener without drug's epoxide moiety, was reported have negligible biochemical activity [Mooberry et al. (1999) Cancer Res. 59, 653−660]. We report here binds at site polymer distinct from taxoid site. found laulimalide,...