- Synthesis and biological evaluation of optimized inhibitors of the mitotic kinesin Kif18A
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The mitotic spindle, a highly dynamic structure composed of microtubules, mediates the segregation of the previously duplicated genome into the two nascent daughter cells. Errors in this process contribute to pathology including tumor formation. Key for the shape and function of the mitotic spindle are kinesins, molecular motor proteins that convert chemical energy into mechanical work. Due to their fast mode of action, small molecules are valuable tools to dissect the dynamic functions of kinesins during mitosis. In this study, we report the identification of optimized small molecule inhibitors of the mitotic kinesin Kif18A. Using BTB-1, the first identified Kif18A inhibitor, as a lead compound, we synthesized a collection of derivatives. We demonstrate that some of the synthesized derivatives potently inhibited the ATPase activity of Kif18A with a half maximal inhibitory concentration (IC50) value in the low micromolar range. In vitro analysis of a panel of Kif18A-related kinesins revealed that the two most potent compounds show improved selectivity compared to BTB-1. Structure-activity relationship studies identified substituents mediating undesired inhibitory effects on microtubule polymerization. In summary, our study provides key insights into the mechanism of action of BTB-1 and its analogs, which will have a great impact on the further development of highly selective and bioactive Kif18A inhibitors. Since Kif18A is frequently overexpressed in solid tumors, such compounds are not only of great interest for basic research but also have the potential to open up new strategies for the treatment of human diseases.
- Braun, Joachim,M?ckel, Martin M.,Strittmatter, Tobias,Marx, Andreas,Groth, Ulrich,Mayer, Thomas U.
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p. 554 - 560
(2015/04/21)
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- Microwave-promoted TBAF-catalyzed SNAr reaction of aryl fluorides and ArSTMS: An efficient synthesis of unsymmetrical diaryl thioethers
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Microwave irradiation was found to promote tetrabutylammonium fluoride catalyzed nucleophilic aromatic substitution of aryl fluorides and arylthiotrimethylsilanes, affording high yields of unsymmetrical diaryl thioethers efficiently under mild, transition-metal- and base-free conditions. Microwave showed unusual improvement on the reaction in not only the conditions and reaction rate, but also in selectivity and substrate scope. Georg Thieme Verlag Stuttgart - New York.
- Liu, Chuanzhi,Zang, Xufeng,Yu, Baohua,Yu, Xiaochun,Xu, Qing
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supporting information; experimental part
p. 1143 - 1148
(2011/07/09)
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- The [Cu]-catalyzed SNAR reactions: Direct amination of electron deficient aryl halides with sodium azide and the synthesis of arylthioethers under Cu(II) - Ascorbate redox system
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A one pot [Cu]-promoted SNAr reaction of electron-deficient halobenzenes with sodium azide and the reduction of the intermediate aryl azides under the same Cu(II)-ascorbate redox conditions leading to anilines has been documented. Control experiments revealed that both ascorbate and proline play important role in the reaction path way. Further, the use of this catalytic Cu(II)-ascorbate redox system has been explored for the synthesis of arylthioethers.
- Goriya, Yogesh,Ramana
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experimental part
p. 7642 - 7650
(2010/12/19)
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- TBAF-catalysed facile synthesis of unsymmetrical diaryl thioethers via mild SNAr reactions
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By using tetrabutylammonium fluoride as the catalyst, the synthesis of unsymmetrical diaryl thioethers could be easily achieved in high yields via a mild nucleopilic aromatic substitution reaction of aryl fluorides and phenylthiotrimethylsilane.
- Yu, Baohua,Zang, Xufeng,Yu, Xiaochun,Xu, Qing
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experimental part
p. 351 - 353
(2010/10/04)
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- Copper(I)-catalyzed S-arylation of thiols with activated aryl chlorides on water
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Copper chloride-catalyzed S-arylation of arenethiols is effected with activated aryl chlorides in neat water by using ethylenediamine as the pair ligand/base. This convenient, environmentally more friendly procedure for the coupling of aryl chlorides allows the arylation between sterically demanding coupling partners.
- Herrero, María Teresa,SanMartin, Raul,Domínguez, Esther
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experimental part
p. 1500 - 1503
(2009/05/07)
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- Simple and efficient recyclable catalytic system for performing copper-catalysed S-arylation reactions in the presence of water
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A novel protocol for the copper-catalysed S-arylation of thiophenol derivatives with aryl halides leading to diaryl sulfides is reported. The reactions were catalysed by a combination of a copper salt and a 1,2-diamine derivative (acting both as the ligand and as the base) using exclusively water as the solvent. The recovery and successful reutilisation of the aqueous medium containing the active catalyst is described. Furthermore, one example of a "one-pot" process involving Br/I exchange of an aryl bromide and further S-arylation is presented.
- Carril, Monica,SanMartin, Raul,Dominguez, Esther,Tellitu, Imanol
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p. 5100 - 5105
(2008/02/09)
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- Spectral studies of substituent effects in some diphenyl sulfide derivatives
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Hammett relationship for λn-π* indicates that substituent effects are purely polar while 1H NMR studies suggest that 4′-arylthio-3′-nitrobenzotrifluoride 4a-i do not exist in the skew conformation. Lynch and dual substituent parameters (DSP) correlations indicate a resonance between the sulfur atom and 3′-nitro group.
- Batterjee
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p. 1471 - 1477
(2007/10/03)
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- 10,11-Dihydro-dibenzo(b,f)thiepin derivatives
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Dibenzothiepin derivatives of the general formula STR1 wherein m, n, R1, R2, R3 and X are as hereinafter set forth, And salts thereof as well as processes for their manufacture are disclosed. The end products are useful as central-depressant and neuroleptic agents.
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