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European journal of medicinal chemistry v.143, 2018년, pp.1028 - 1038   SCI SCIE
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Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity

Solomon, V. Raja (Health Sciences North Research Institute, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada ) ; Pundir, Sheetal (Health Sciences North Research Institute, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada ) ; Le, Hoang-Thanh (Health Sciences North Research Institute, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada ) ; Lee, Hoyun (Health Sciences North Research Institute, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada ) ;
  • 초록  

    Abstract In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin-9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one ( 25 ; VR151 ) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans. Our data showed that cancer cells are arrested in S phase for a prolonged period due to the down-regulation of DNA replication, leading to eventual cell death. We have also shown that the S phase arrest may be resulted by the down-regulation of cyclin A coupled with the continued up-regulation of cyclin E, which coincide with the down-regulation of mTor-S6K and mTor-4EBP1 pathways. Highlights A series of novel quinacrine derived thiazinan-4-ones were synthesized. The detailed SARs of the derivatives were summarized. Compound 25 is substantially effective than the parental quinacrine. Compound 25 bind to certain protein essential for DNA replication without causing DNA damage, resulting in the inhibition of DNA replication and/or the down-regulation of cyclin A. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    9-Aminoacridine .   Hybrid molecules .   Anticancer agents .   Cyclins .   S phase arrest .   Inhibition of DNA replication.  

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