Improving the Hsp90 Inhibitors Containing 4-(2,4-Dihydroxyphenyl)-1,2,3- thiadiazole Scaffold: Synthesis, Affinity and Effect on Cancer Cells
2017
Background: Human Hsp90 chaperone inhibitors are known to be potential anticancer drugs. Previously we
have shown a couple of 5-aryl-4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazoles to be promising anticancer agents.
Objective: To improve the compounds containing 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold as human Hsp90
inhibitors.
Methods: We employed chemical synthesis to obtain new compounds and assayed their binding to Hsp90 using the
fluorescence thermal shift assay and used MTT assays to determine their effect on cancer cells.
Results: A series of compounds containing the 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold were synthesized as
Hsp90 inhibitors. Analysis of their binding to the recombinant N-terminal domain of Hsp90 revealed that four of these
compounds bound to Hsp90 with Kd of 0.6 to 0.8 nM. The compounds fully inhibited the growth of all tested cancer
cell lines: A549 (lung adenocarcinoma), IGR39 (melanoma), and U87 (glioblastoma), with the effective
antiproliferative concentration (EC50) of the compounds reaching 0.35 μM.
Conclusion: This series of 14 novel and efficient Hsp90 inhibitors provided additional information on the structureactivity
relationship of Hsp90 inhibitors and may be further developed into drugs targeting Hsp90.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
5
Citations
NaN
KQI