02442nab a2200265 i 4500 publ16130 20190716135552.0 190716s2019 hu o 0|| zxx d 1747-0277 10.1111/cbdd.13473 doi 30409869 mtmt SZTE Publicatio Repozitórium hun zxx Żesławska Ewa Pharmacophoric features for a very potent 5-spirofluorenehydantoin inhibitor of cancer efflux pump ABCB1, based on X-ray analysis [elektronikus dokumentum] / Żesławska Ewa 2019 844-853 CHEMICAL BIOLOGY & DRUG DESIGN 93 No. 5 In order to extend knowledge about pharmacophoric features responsible for ABCB1 inhibitory properties of imidazolidin-2,4-dione derivatives, 1'-[4-(4-(o-methoxyphenyl)-piperazin-1-yl)butyl]-3'-methyl-spiro(fluoren-9,5'-imidazolidine)-2',4'-dione (3) and its salt (4) with rhodanine-3-acetic acid (RA) were prepared and investigated by X-ray diffraction method, as well as their efflux modulating effects in cancer cells (mouse T-lymphoma), cytotoxic and antiproliferative activities were evaluated in vitro. The molecular geometry, intermolecular interactions and crystal packing of base and acid forms of 3 were analyzed to see, if conformational changes influence the biological activities. The geometry of 2-methoxyphenylpiperazine and 5-spirofluorenehydantoin moieties was compared with other crystal structures containing these fragments. Our results indicated a very potent inhibitory action on ABCB1 pump, and significant cytotoxic and antiproliferative properties of 3 in T-lymphoma, even more potent in the case of MDR cells. Furthermore, the compound 3 converted into the salt 4 of inactive acid (RA) has maintained both, the efflux pump inhibitory and antiproliferative activities, showing strong synergism with doxorubicin. A comparison of geometry of 3 in both crystal structures (3 and 4) shows a significant difference in the arrangement of piperazine ring with respect to the aliphatic linker. This article is protected by copyright. All rights reserved. Kincses Annamária aut Spengler Gabriella aut Nitek Wojciech aut Tejchman Waldemar aut Handzlik Jadwiga aut http://publicatio.bibl.u-szeged.hu/16130/1/-es-awska_et_al-2019-Chemical_Biology__Drug_Design.pdf Dokumentum-elérés