ライフサイエンスコーパス: epothilone

1 g those that are resistant to paclitaxel and epothilone.

2 strain of Sorangium cellulosum that produces epothilone.

3 poxidase that converts desoxyepothilone into epothilone.

4 sites of interaction with paclitaxel and the epothilones.

5 -tubulin, similar data are not available for epothilones.

6 lyzes formation of the thiazole found in the epothilones.

7 a common pharmacophore shared by taxanes and epothilones.

8 on pharmacophore model between Taxol and the epothilones.

9 ant ovarian line retained sensitivity to the epothilones.

10 tivity similar to that of paclitaxel and the epothilones.

11 er, and remarkable potency relative to other epothilones.

12 The isolation of epothilone 490 (3) prompted us to reevaluate the utility

13 the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promis

14 ydro-12,13-desoxyepothilone B ([16]ddEpoB or epothilone 490).

15 h (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose po

16 However, we found that epothilone A and B do stimulate the formation of microtu

17 The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-

18 modes of binding that have been proposed for epothilone A in the taxane pocket of beta-tubulin.

19 ines derived in a single-step selection with epothilone A or B.

20 had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usual

21 Photoaffinity labeling with an epothilone A photoprobe led to the identification of the

22 difference observed between laulimalide and epothilone A was that only laulimalide was able to enhan

23 ivity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel.

24 Eleutherobin and epothilone A were competitive inhibitors of the binding

25 hat the polymers formed with laulimalide and epothilone A were more stable at 0 degrees C.

26 ) the high resolution cocrystal structure of epothilone A with an alpha,beta-tubulin complex and for

27 n the resistant lines); and eleutherobin and epothilone A, 10-40 nM.

28 increased drug sensitivity did not extend to epothilone A, a drug that binds to the same site and has

29 Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with pacli

30 laulimalide, while as active as paclitaxel, epothilone A, and eleutherobin in promoting the assembly

31 The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabil

32 we report the first solid-phase synthesis of epothilone A, the total synthesis of epothilone B, and t

33 differ greatly from those of paclitaxel and epothilone A.

34 ve against cells resistant to paclitaxel and epothilone A.

35 These precursors were then converted to epothilones A (1) and C (3) to complete the total synthe

36 lyst has been used in the total synthesis of epothilones A (1) and C (3).

37 rystallography in 1996, several syntheses of epothilones A and B have been reported, indicative of th

38 gainst cell lines resistant to paclitaxel or epothilones A and B on the basis of mutations in the M40

39 The apparent Ki values for epothilones A and B were 1.4 and 0.7 microM by Hanes ana

40 y identified natural products, eleutherobin, epothilones A and B, and discodermolide.

41 Epothilones A and B, natural products with minimal struc

42 the epoxidation of epothilones C and D into epothilones A and B, respectively.

43 or the epoxidation of epothilones C and D to epothilones A and B, respectively.

44 Epothilones A and B, two compounds that have been recent

45 The principal natural compounds are epothilones A and B, which have an epoxide in the macroc

46 ctinomycete Streptomyces coelicolor produced epothilones A and B.

47 a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleuthero

48 The biosynthesis of epothilones, a family of hybrid polyketide (PK)/nonribos

49 crotubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth.

50 We compared the efficacy of Flu with the epothilone analog 12,13-desoxyepothilone B (dEpoB) in xe

51 Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of natur

52 Ixabepilone is the first epothilone analogue to receive US Food and Drug Administ

53 The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) i

54 A new epothilone analogue, 12,13-desoxyepothilone F (dEpoF, 21

55 dicated by the activity of a potent pyridine-epothilone analogue.

56 on of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described.

57 sized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tub

58 l for the precursor-directed biosynthesis of epothilone analogues and related complex polyketides.

59 We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functiona

60 and the engineering of EpoK to prepare novel epothilone analogues.

61 PKS and the generation of novel biosynthetic epothilone analogues.

62 The natural products epothilone and bleomycin are assembled by hybrid polyket

63 ccount, we focus on the relationship between epothilone and paclitaxel in the context of tumors with

64 ng a role for novel chemotherapies including epothilones and immunomodulators (IMiDs), as well as oth

65 e calcitriol, growth factor-targeted agents, epothilones and others.

66 in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar me

67 Natural epothilones and their analogs promote tumor cell death b

68 The unification of taxane, epothilone, and sarcodictyin chemistries in a single pha

69 reveal tubulin interactions with Taxol, the epothilones, and other Taxol-like compounds.

70 lation, and cell death caused by paclitaxel, epothilones, and vinblastine.

71 othilone-resistant sublines exhibit impaired epothilone- and taxane-driven tubulin polymerization cau

72 Epothilones are a class of chemotherapy that target micr

73 The epothilones are a family of polyketide natural products

74 The epothilones are a group of novel microtubule-targeted, a

75 The epothilones are a new class of highly promising anticanc

76 Epothilones are a new class of nontaxane tubulin polymer

77 The epothilones are a new class of tubulin-polymerizing agen

78 The epothilones are a novel class of nontaxane microtubule-s

79 The epothilones are a novel class of nontaxane, microtubule-

80 Paclitaxel (Taxol) and the epothilones are antimitotic agents that promote the asse

81 The epothilones are competitive inhibitors of the binding of

82 ed, bortezomib, TLK286, bevacizumab, and the epothilones are currently being evaluated in non-small c

83 not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor

84 The epothilones are naturally occurring antimitotic drugs th

85 The epothilones are naturally occurring, cytotoxic macrolide

86 The epothilones are positioned with the macrolide ring rough

87 The epothilones are potent anticancer natural products produ

88 Epothilones are potential anticancer drugs that stabiliz

89 Epothilones are thiazole-containing natural products wit

90 ng agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic agents for t

91 For the first time in the epothilone area, the new synthesis exploits the power of

92 The single NRPS module of the epothilone assembly line, EpoB, is a distinct subunit of

93 ure combinatorial biosynthetic variations in epothilone assembly may be feasible.

94 dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) hav

95 and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) s

96 eld epothilone D (4) and, after epoxidation, epothilone B (2).

97 total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-deso

98 2,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam).

99 Epothilone B (BMS-247550) is a semisynthetic analog of t

100 loaded with a potent chemotherapeutic agent [epothilone B (EB)] showed significantly lower systemic t

101 rotubule stabilizing agents such as taxanes, epothilone B (EpoB) has merit, especially in combination

102 rier-permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spi

103 Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expressio

104 At 2 nM epothilone B (IC(33)), the mean growth and shortening ra

105 At these doses, Epothilone B also caused regression of vessels in wells

106 Ixabepilone is an epothilone B analog that binds to microtubules and resul

107 Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has

108 ne (BMS-247550) is a microtubule-stabilizing epothilone B analog with activity in taxane-resistant me

109 MDA, including epothilone B analogue (BMS-247550) and vinblastine, indu

110 We show that BMS-247550 (EpoB), a novel epothilone B analogue, induces cell cycle arrest at the

111 l evaluation of a series of 12,13-aziridinyl epothilone B analogues is described.

112 hibitors of the binding of both radiolabeled epothilone B and paclitaxel to microtubules.

113 Treatment of tumors or normal tissues with Epothilone B at doses less than 10-8 mol/L was ineffecti

114 ation of HIF-1alpha in parental 1A9 cells at epothilone B concentrations that induced extensive micro

115 material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation

116 axel-sensitive human cell lines we examined, epothilone B had greater antiproliferative activity than

117 Aza-epothilone B has been advanced to phase I clinical trial

118 acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrat

119 protein was shown to convert epothilone D to epothilone B in vitro.

120 Furthermore, epothilone B inhibited HIF-1 transcriptional activity in

121 Epothilone B is a novel nontaxane antimicrotubule agent

122 Epothilone B may be an effective antiangiogenic agent in

123 Thus, the effects of epothilone B on microtubule dynamics are remarkably simi

124 Comparison of the effects of epothilone B on microtubule dynamics with those of pacli

125 On the other hand, epothilone B prevented microtubule disruption and inhibi

126 Conversely, epothilone B reactivated neuronal polarization by induci

127 In addition, epothilone B severely dampens the dynamics of yeast micr

128 We found that epothilone B suppressed microtubule dynamics in a concen

129 cessfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam)

130 network disruption, we tested the ability of epothilone B to inhibit HIF-1alpha protein in the human

131 Epothilone B treatment at doses of 10-6 mol/L and 10-8 m

132 Our data showed that epothilone B treatment down-regulated HIF-1alpha protein

133 In contrast, epothilone B treatment had no effect on either microtubu

134 bule bundles appeared more rapidly following epothilone B treatment, and there were different proport

135 atin and 7-epi-dictyostatin displaced [(14)C]epothilone B with K(i) values of 480 and 930 nM, respect

136 al bovine serum alone or in combination with Epothilone B, a tubulin inhibitor with antiangiogenic pr

137 In contrast, epothilone B, an agent to which the resistant cells reta

138 rotubule-stabilizing agents including Taxol, epothilone B, and discodermolide produce aneuploid popul

139 cs, including cancer drugs, such as taxanes, epothilone B, and modulators of the estrogen pathway.

140 esis of epothilone A, the total synthesis of epothilone B, and the generation of a small epothilone l

141 was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine.

142 ubule-disrupting agents, including taxotere, epothilone B, discodermolide, vincristine, 2-methoxyestr

143 At 0.2 nM epothilone B, dynamics were not significantly altered.

144 in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule sta

145 e a comprehensive analysis of the effects of epothilone B, ixabepilone (IXEMPRA(TM)), laulimalide, an

146 rotubule dynamics at three concentrations of epothilone B, one that induced no mitotic arrest (0.2 nM

147 No resistance was observed to paclitaxel and epothilone B, polymerizing agents (0.89- to 1.14-fold).

148 constant (K(i)) determinations using [(14)C]epothilone B, which has a 3-fold higher affinity for the

149 es reported here for the epothilone D-bound, epothilone B-bound, and substrate-free forms, respective

150 y further explores the mechanisms underlying epothilone B-mediated cytotoxicity in human breast cance

151 h aneuploid populations are diminished in an epothilone B-resistant cell line.

152 semisynthetic analog of the natural product epothilone B.

153 d by 54% by paclitaxel compared with 62% for epothilone B.

154 arian carcinoma cell line) approach those of epothilone B.

155 ly reduced cellular cytotoxicity compared to epothilone B.

156 imizes the properties of naturally occurring epothilone B.

157 semisynthetic analog of the natural product epothilone B.

158 A convergent, total synthesis of epothilones B (2) and D (4) is described.

159 Preclinical studies indicate that epothilones bind to and stabilize microtubules in a mann

160 ted that the azide analogues can bind to the epothilone binding site, but that the benzophenone analo

161 sed current models describing paclitaxel and epothilone binding to mammalian beta-tubulin to explain

162 To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resi

163 vely, are the first crystal structures of an epothilone-binding protein.

164 a heme containing monooxygenase involved in epothilone biosynthesis in the myxobacterium Sorangium c

165 The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium c

166 s combined with the first two enzymes of the epothilone biosynthesis pathway, the acyl carrier protei

167 ible for thiazoline to thiazole oxidation in epothilone biosynthesis, and expressed it in soluble for

168 and EpoB, to reconstitute the early steps in epothilone biosynthesis.

169 The epothilone biosynthetic gene cluster was isolated from S

170 Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to bas

171 d through the stereoselective preparation of epothilone C and nakadomarin A, the previously reported

172 ill facilitate improvements in the yields of epothilones C and D and the engineering of EpoK to prepa

173 ium cellulosum, catalyzes the epoxidation of epothilones C and D into epothilones A and B, respective

174 The epoxidation of epothilones C and D to A and B, respectively, is mediate

175 50 enzyme responsible for the epoxidation of epothilones C and D to epothilones A and B, respectively

176 biosynthesis, resulting in the production of epothilones C and D.

177 and epoF genes also led to the production of epothilones C and D.

178 acyl donor for subsequent elongation of the epothilone chain.

179 ncise modular laboratory construction of the epothilone class of promising antitumor agents has been

180 The entire synthetic epothilone cluster was then expressed in a strain of E.

181 cing a soluble protein from all genes in the epothilone cluster.

182 diverse antimitotic compounds, including the epothilones, compete with Taxol for binding to mammalian

183 The epothilones competitively inhibit the binding of paclita

184 ed, one mode was identified as the preferred epothilone conformation as indicated by the activity of

185 ically synthesizing and evaluating synthetic epothilone congeners that are not accessible through mod

186 of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone.

187 Epothilones could be efficacious as an additional therap

188 as selectively reduced with diimide to yield epothilone D (4) and, after epoxidation, epothilone B (2

189 convergent and stereocontrolled synthesis of epothilone D (4) is reported.

190 rization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the syn

191 of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau

192 onstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequen

193 e report that relatively low weekly doses of Epothilone D also partially reversed the impaired explor

194 An alternative route to epothilone D employed alkyne 39, obtained from 33, in a

195 However, thus far epothilone D has been the only brain-penetrant MT-stabil

196 ted 1 h with microtubule stabilizing agents, epothilone D or discodermolide, followed by dosing with

197 Epothilone D similarly mitigated the effects of a clinic

198 nd the purified protein was shown to convert epothilone D to epothilone B in vitro.

199 Three photoaffinity labeled derivatives of epothilone D were prepared by total synthesis, using eff

200 Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural p

201 5-A crystal structures reported here for the epothilone D-bound, epothilone B-bound, and substrate-fr

202 The epothilones differ in their ability to retain activity a

203 or microtubules from S. cerevisiae, whereas epothilone does.

204 phore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and ratio

205 t of the mitochondrial pathway of apoptosis, epothilone (Epo) B derivative BMS 247550, a novel nontax

206 and the nontaxane tubulin-polymerizing agent epothilone (Epo) B were also determined in MB-468 cells.

207 A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated f

208 iamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance.

209 ction protocol in efficiently generating the epothilone framework.

210 In addition to identifying fragments of the epothilone gene cluster, we obtained 11 unique fragments

211 poK, a cytochrome P450 enzyme encoded in the epothilone gene cluster.

212 The design of the synthetic epothilone genes together with E. coli expression provid

213 Epothilones have emerged from these efforts as a promisi

214 With recent clinical approval, epothilones hold promise for clinical use after CNS inju

215 e a strong rationale for testing taxanes and epothilones in clinical trials targeting HIF-1 in cancer

216 tigen for patupilone and sagopilone, current epothilones in development, along with those of ixabepil

217 e for the precursor-directed biosynthesis of epothilones in Escherichia coli.

218 group at C21, exhibits advantages over other epothilones in terms of water solubility, and can serve

219 tivity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully exp

220 We hypothesize that epothilones induce mitotic arrest by suppressing microtu

221 ing agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity.

222 lizers, which in contrast to taxanes and the epothilones interact preferentially with the mutant tubu

223 The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to f

224 The polyketide epothilone is a potential anticancer agent that stabiliz

225 epothilone B, and the generation of a small epothilone library.

226 The epothilones, like paclitaxel, induced tubulin to form mi

227 sition is examined by application of a Taxol-epothilone minireceptor, K(i) estimation for microtubule

228 Interestingly, for epothilone module 8, use of dimethylmalonyl-ACP appeared

229 tion mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantag

230 ngly, there are strong parallels between the epothilone/P450epoK and paclitaxel/tubulin interactions.

231 ether with solution-phase synthesis of other epothilones, paves the way for the generation of large c

232 or both the biochemical investigation of the epothilone PKS and the generation of novel biosynthetic

233 Here the third enzyme involved in epothilone production, the five domain 195 kDa polyketid

234 in the discovery of some of the most potent epothilones reported to date.

235 The epothilones represent a promising class of natural produ

236 Significantly, paclitaxel- and epothilone-resistant cell lines were less resistant to t

237 in native tubulins isolated from Taxol- and epothilone-resistant cell lines.

238 bilized microtubules from parental and Taxol/epothilone-resistant human cancer cell lines.

239 for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines de

240 er cell line 1A9 and its beta-tubulin mutant epothilone-resistant subclone 1A9/A8.

241 These epothilone-resistant sublines exhibit impaired epothilon

242 inically useful biological properties to the epothilone scaffold.

243 ions of ring-closing metathesis reactions in epothilone settings led to the first and second generati

244 est, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, novios

245 The complex explains both the broad-based epothilone structure-activity relationship and the known

246 Similar studies with the epothilones suggest that the current tubulin-binding mod

247 Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by com

248 ped a system comprised of modules 6-9 of the epothilone synthetase for the precursor-directed biosynt

249 The epothilone synthetase is a decamodular megasynthase resp

250 t example of a 17-membered ring macrolactone epothilone that has retained its antitumor activity.

251 ased on structural similarities, a plausible epothilone tubulin-binding mode is proposed.

252 ing one of the two principal subunits of the epothilones, was prepared from propargyl alcohol via hep

253 synthase (PKS) modules of yersiniabactin and epothilone were characterized using mass spectrometry.

254 Although two binding modes for the epothilones were predicted, one mode was identified as t

255 dification of any of the naturally occurring epothilones, were discovered through total chemical synt

256 investigated the conformational behavior of epothilone, which led to the identification of a common

257 We examined interactions of the epothilones with purified tubulin and additional cell li

258 tubulin; thus, it would be expected that the epothilones would not affect yeast microtubules.