title: Improving the Hsp90 Inhibitors Containing 4-(2,4-Dihydroxyphenyl)-1,2,3-thiadiazole Scaffold: Synthesis, Affinity and Effect on Cancer Cells.
abstract: 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.
  
  
  CONCLUSIONS
  This series of 14 novel and efficient Hsp90 inhibitors provided additional information on the structure-activity relationship of Hsp90 inhibitors and may be further developed into drugs targeting Hsp90.
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Sauletekio 7, Vilnius LT-10257, Lithuania.
authors.forename: Egidijus
authors.initials: E
authors.lastname: Kazlauskas
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania.
authors.forename: Algirdas
authors.initials: A
authors.lastname: Brukstus
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Sauletekio 7, Vilnius LT-10257, Lithuania.|Department of Drug chemistry, Faculty of Pharmacy, Lithuanian University of Health Sciences, Mickeviciaus 9, Kaunas LT-44307, Lithuania.
authors.forename: Herkus
authors.initials: H
authors.lastname: Petrikas
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Sauletekio 7, Vilnius LT-10257, Lithuania.
authors.forename: Vilma
authors.initials: V
authors.lastname: Petrikaite
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania.
authors.forename: Inga
authors.initials: I
authors.lastname: Cikotiene
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Sauletekio 7, Vilnius LT-10257, Lithuania.
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D012118:Resorcinols; D013830:Thiadiazoles
keywords: Anticancer; Hsp90; MTT assay.; differential scanning fluorimetry; fluorescence thermal shift assay; ligand binding; thermofluor; thiadiazole