New synthetic inhibitors of microtubule depolymerization

Klar, Ulrich; Graf, Hermann; Schenk, Oliver; Röhr, Bodo; Schulz, Horst

doi:10.1016/s0960-894x(98)00226-1

Cited by 42 publications

(26 citation statements)

References 18 publications

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“…Both map near the taxane-binding site in the atomic model of tubulin (24). However, strong binding to tubulin does not necessarily cause efficient inhibition of tumor cell growth, as has been demonstrated for a new class of microtubulestabilizing substances (25).…”

Section: Discussionmentioning

confidence: 87%

Subcellular distribution of epothilones in human tumor cells

Lichtner¹,

Rotgeri²,

Bunte³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Epothilones are a new class of natural and potent antineoplastic agents that stabilize microtubules. Although 12,13-epoxide derivatives are potent antiproliferative agents, the activities of the corresponding 12,13-olefin analogs are significantly decreased. These data were confirmed for two new analogs, 6-propyl-EpoB (pEB) and 6-propyl-EpoD (pED), in comparison with the natural compounds EpoB͞EpoD, by using human A431, MCF7, and MDR1-overexpressing NCI͞Adr cells. By using tritiated pEB͞pED, compound uptake, release, and nuclear accumulation were investigated in A431 and NCI͞Adr cells. In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1. The degree of export depends on the structure, olefin vs. epoxide-analog, and also on the intracellular drug concentration. The accumulation of pED used at 3.5 or 70 nM, respectively, was increased in the presence of 10 M Verapamil in both cell lines 2-to 8-fold. In contrast, the intracellular levels of pEB were affected by Verapamil only at 3.5 nM pEB in NCI͞Adr (2-fold) and not in A431 cells. In addition, strong nuclear accumulation was observed for pEB (40 -50%) but not paclitaxel or pED (5-15%) in both cell lines. Our study suggests that differences in growth inhibitory efficacy between epoxide and olefin analogs may be based on different mechanisms of drug accumulation and subcellular distribution. Epothilones are a new class of natural products and potential antineoplastic agents. Although they have no structural similarities to taxanes, they exert cellular effects similarly to paclitaxel (Taxol). Thus, epothilones bind to tubulin and cause hyperstabilization of microtubules with subsequent mitotic arrest and apoptotic cell death (1-3). The molecular mechanisms by which epothilones and paclitaxel induce apoptosis remain to be elucidated.It has been demonstrated that epothilones are generally superior to paclitaxel in their ability to inhibit the proliferation of human cancer cell lines that are resistant to commonly used anticancer agents, including paclitaxel. The best understood mechanism of resistance to cytotoxic drugs, including antimicrotubule agents is drug export by multidrug-resistant pglycoprotein (MDR1) (4). Although taxanes are substrates for MDR1, epothilones are not, and thus MDR1-positive tumor cells remain sensitive to epothilones (1, 2, 5-9).The 12,13-epoxide moiety of epothilone A (EpoA) and B (EpoB) is dispensable for tubulin͞microtubule-related effects in vitro, because the corresponding olefin analogs (EpoC and EpoD), as inducers of tubulin polymerization, are equally potent to EpoA and EpoB (7,8,10). Formal removal of epoxide oxygen in EpoB, thus leading to EpoD, does cause a significant decrease (ϳ10-to 30-fold) in antiproliferative activity (9). Furthermore, exposure of tumor cells to EpoB for a 4-h period produces virtually the same growth inhibitory effect as a continuous 3-day exposure, whereas for EpoD, exposure times more than 4 h were required to produce ef...

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Section: Discussionmentioning

confidence: 87%

Subcellular distribution of epothilones in human tumor cells

Lichtner¹,

Rotgeri²,

Bunte³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Epo A, a macrolide isolated from Sorangium cellulosum, also exhibited MT-stabilizing activity comparable to paclitaxel as has been reported by others (Bollag et al, 1995). A synthetic compound designated as "UK-100" is a nontaxoid borneol derivative with MT-stabilizing activity comparable to paclitaxel but markedly reduced cytotoxicity in cancer cell lines (Klar et al, 1998), and discodermolide, a marine sponge product, was also quite similar to paclitaxel in MT-assembly, although it is structurally unrelated (Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

“…UK-100 (Klar et al, 1998) was a gift from Schering AG, Berlin, Germany, and discodermolide was a gift from Novartis Pharmaceutical Co., East Hanover, NJ. The succinylated paclitaxel analog Tx-67 was prepared by parallel solution phase synthesis as previously described (Liu et al, 2002).…”

Section: Methodsmentioning

confidence: 99%

β-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents

Michaelis

Ansar

Chen

et al. 2004

J Pharmacol Exp Ther

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Deposition of ␤-amyloid peptide (A␤) and hyperphosphorylation of the protein are associated with neuronal dysfunction and cell death in Alzheimer's disease. Although the relationship between these two processes is not yet understood, studies have shown that both in vitro and in vivo exposure of neurons to A␤ leads to hyperphosphorylation and neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel (Taxol) protects primary neurons against toxicity induced by the A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide. The studies in this report were undertaken to characterize the actions of paclitaxel more fully, to assess the effectiveness of structurally diverse microtubulestabilizing agents in protecting neurons, and to determine the time course of the protective effects of the drugs. Primary neurons were exposed to A␤ in the presence or absence of several agents shown to interact with microtubules, and neuronal survival was monitored. Paclitaxel protected neurons against A␤ 1-42 toxicity, and paclitaxel-treated cultures exposed to A␤ showed enhanced survival over A␤-only cultures for several days. Neuronal apoptosis induced by A␤ was blocked by paclitaxel. Other taxanes and three structurally diverse microtubule-stabilizing compounds also significantly increased survival of A␤-treated cultures. At concentrations below 100 nM, the drugs that protected the neurons did not produce detectable toxicity when added to the cultures alone. Although multiple mechanisms are likely to contribute to the neuronal cell death induced by oligomeric or fibrillar forms of A␤, low concentrations of drugs that preserve the integrity of the cytoskeletal network may help neurons survive the toxic cascades initiated by these peptides.

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“…In addition, this compound inhibits rat bone resorption 14 , by inhibiting the formation of osteoclasts 15 , and causes microtubule depolymerization. 16 Several terpenoid compounds have demonstrated antiprotozoal activity against T. cruzi.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial activity of synthetic bornyl benzoates againstTrypanosoma cruzi

Corrêa

Miranda

Duarte

et al. 2012

Pathogens and Global Health

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We report here for the first time the in vitro effects of (1S,2R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-yl-39,49,59-trimethoxy benzoate (1) and (1S,2R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-yl benzoate (2) on the growth and ultrastructure of Trypanosoma cruzi. These two synthetic compounds exerted an antiproliferative effect on the epimastigote forms of the parasite. The ICs 50/72h of two synthetic L-bornyl benzoates, 1 and 2, was 10.1 and 12.8 mg/ml, respectively. Both compounds were more selective against epimastigotes than HEp-2 cells. Ultrastructural analysis revealed intense cytoplasmic vacuolization and the appearance of cytoplasmic materials surrounded by membranes. The treatment of peritoneal macrophages with compounds 1 and 2 caused a significant decrease in the number of T. cruzi-infected cells. L-Bornyl benzoate derivatives may serve as a potential source for the development of more effective and safer chemotherapeutic agents against T. cruzi infections.

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New synthetic inhibitors of microtubule depolymerization

Cited by 42 publications

References 18 publications

Subcellular distribution of epothilones in human tumor cells

Subcellular distribution of epothilones in human tumor cells

β-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents

Antimicrobial activity of synthetic bornyl benzoates againstTrypanosoma cruzi

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