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Geldanamycin and derivatives inhibit cancer invasion and identify novel targets

A compound, cancer cell technology, applied in the field of cancer pharmacology, which can solve the problem of not providing anti-tumor effect and so on

Inactive Publication Date: 2007-07-11
VAN ANDEL RES INST +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This compound is said to inhibit the growth of SKBr3 breast cancer cells in vivo, although no results were provided at what concentration level the antitumor effect was

Method used

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  • Geldanamycin and derivatives inhibit cancer invasion and identify novel targets
  • Geldanamycin and derivatives inhibit cancer invasion and identify novel targets
  • Geldanamycin and derivatives inhibit cancer invasion and identify novel targets

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Experimental program
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Embodiment 1-19

[0235] Synthesis and / or Characterization of Geldanamycin and Derivatives

[0236] general method. Melting points are unmodified. Infrared spectra were recorded on a Matton Galaxy Series FTIR 3000 spectrophotometer. UV-vis spectra were recorded on a Hitachi U-4001 spectrophotometer. Recorded on a Varian Inova-600, UnityPlus-500, VRX-500 or VRX-300 spectrometer 1 H and 13 CNMR spectrum. The numbering used in all assignments is based on the GA ring system (Sasaki, K et al., J. Ain. Clzem. Soc. 92:7591 (1970)), unless otherwise stated). Mass spectra were performed by MSU Mass Spectrometry Facility. GA and macbecinII were provided by National Cancer Institutes. Macbecin I was synthesized from macbecin II by a published procedure (Muroi, M et al., 1980). Radicicol is commercially available (Sigma-Aldrich). Anhydrous solvents were purified using standard methods.

Embodiment 1

[0238] (+)-Geldanamycin (1)

[0239] IR(CH 2 Cl 2 )(cm -1 )3535, 3421, 3364, 3060, 2989, 2968, 1733, 1690, 1650, 1603, 1500, 1367, 1284, 1262, 1193, 1135, 1098, 1054; 1 H NMR (CDCl 3 , 500MHz, assigned with COZY) δ8.69 (s, IH) (22-NH), 7.27 (s, 1H) (19-H), 6.92 (bd, J = 11.5Hz, 1H) (3-H) , 6.55 (ddd, J=11.5, 11.0, 1.0Hz, 1H) (4-H), 5.86 (dd, J=11.0, 10.0Hz, 1H) (5-H), 5.80 (bd, J=9.5Hz, 1H)(9-H), 5.17(s,1H)(7-H), 4.77(bs,2H)(7-O2CNH 2 ), 4.29 (bd, J=10.0Hz, 1H) (6-H), 4.10 (s, 3H) (17-OCH 3 ), 3.51(ddd, J=9.0, 6.5, 2.0Hz, 1H)(H-H), 3.37(ddd, J=9.0, 3.0, 3.0Hz, 1H)(12-H), 3.34(s, 3H)(6 - or 12-OCH 3 ), 3.27(s, 3H) (6- or 12-OCH 3 ), 3.03 (bd, J=6.5Hz, IH) (11-OH), 2.76 (dqd, J=9.5, 7.0, 2.0Hz, 1H) (10-H), 2.50-2.39 (m, 2H) (15 -H and H 1 ), 2.00(bs,3H)(2-CH 3 ), 1.81-1.70 (m, 2H) (13-H and H 1 ), 1.77 (d, J=1.0Hz, 3H) (8-CH 3), 1.68-1.60 (m, 1H) (14-H), 0.97-0.93 (m, 6H) (10- and 14-CH 3 ); (Sasaki et al., 1970, supra; Organic Synthesis, Cumulative Volume 4, 433,...

Embodiment 2

[0241] 17-allylamino-17-desmethoxygeldanamycin (4)

[0242] (Schnur, RC et al., 1995a, 1995b) Mix (+)-geldanamycin (5.1 mg, 9.0 mol) with allylamine (10.0 μl, 0.13 mmol) in chloroform (1.5 ml) at room temperature Stir. Based on complete conversion of GA shown by thin layer chromatography (18 h), the mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The product was isolated as a purple solid (5.3 mg, 99%) by flash column chromatography on silica gel (n-hexane / ethyl acetate). IR(KBr)(cm -1 ) 3464, 3333, 2958, 2929, 2825, 1728, 1691, 1652, 1571, 1485, 1372, 1323, 1189, 1101, 1057; UV (95% EtOH) (nm) 332 (ε = 2.0 × 104); 1H NMR (CDCl 3 , 500MHz) δ9.14(s, 1H), 7.28(s, 1H), 6.93(bd, J=11.5Hz, 1H), 6.56(bdd, J=11.5, 11.0Hz, 1H), 6.38(bt, J =6.0Hz, 1H), 5.94-5.81(m, 3H), 5.30-5.24(m, 2H), 5.17(s, 1H), 4.82(bs, 2H), 4.29(bd, J=10.0Hz, 1H) , 4.21 (bs, 1H), 4.18-4.08 (m, 2H), 3.55 (ddd, J=9.0, 6.5, 2.0Hz, 1H), 3.43 (ddd, J=9.0, 3.0, 3.0Hz, 1H), 3...

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Abstract

Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF / SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (>=nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF / SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.

Description

technical field [0001] The invention belongs to the field of cancer pharmacology, and relates to chemical derivatives of geldanamycin (1), wherein some derivatives are new compounds that inhibit the activity of cancer cells at femtomolar concentrations, and these compounds are used to inhibit Use for HGF-dependent, Met-mediated activation, growth, invasion and metastasis of tumor cells. These compounds acting on new but unrecognized targets are very effective anticancer agents. Background technique [0002] Geldanamycin (GA) is a haptomycin natural product drug (Sasaki K et al., 1970; DeBoer C et al., 1970). Geldanamycins (GAs) here refer to a class of GA derivatives, some of which exhibit anticancer activity in mouse xenograft models of human breast cancer, melanoma and ovarian cancer (Schulte TW et al. et al., 1998; Webb CP et al., 2000). Furthermore, drugs of the GA class reduce the expression of several tyrosine kinase and serine kinase oncogene products, including He...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D225/06A61K31/33A61P35/00
CPCC07D225/06A61P13/08A61P35/00A61P35/04
Inventor 谢谦大卫·文克特沈玉钗乔治·F.·范德沃德里克·海
Owner VAN ANDEL RES INST
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