title: Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis.
abstract: Invasive ductal carcinoma is the most common breast malignancies tumors and has tendency to bone metastases. Many oncogenic client proteins involved in formation of metastatic pathways. Stabilization, regulation, and maintenance of these oncogenic client proteins are provided with Heat Shock Protein 90 (Hsp90). Hsp90 perform these processes through its ATP binding and subsequent hydrolysis energy. Therefore, designing Hsp90 inhibitors is a novel cancer treatment method. However, many Hsp90 inhibitors have solubility problems and showed adverse effects in clinical trials. Thus, we designed and synthesized novel pyrimidinyl acyl thiourea derivatives to selectively inhibit Hsp90 alpha in human invasive ductal breast (MCF-7) and human bone osteosarcoma (Saos-2) cell lines. In vitro experiments showed that the compounds inhibited cell proliferation, ATP hydrolysis, and exhibited cytotoxic effect on these cancer cell lines. Further, gene expression was analyzed by microarray studies on MCF-7 cell lines. Several genes that play vital roles in breast cancer pathogenesis displayed altered gene expression in the presence of a selected pyrimidinyl acyl thiourea compound. Molecular docking studies were also performed to determine interaction between Hsp90 ATPase domain and pyrimidinyl acyl thiourea derivatives. The results indicated that the compounds are able to interact with Hsp90 ATP binding pocket and inhibit ATPase function. The designed compounds powerfully inhibit Hsp90 by an average of 1 μM inhibition constant. And further, the compounds perturb Hsp90 N terminal domain proper orientation and ATP may not provide required conformational change for Hsp90 function as evidenced by in silico experiments. Therefore, the designed compounds effectively inhibited both invasive ductal breast carcinoma and bone metastasis. Pyrimidinyl acyl thiourea derivatives may provide a drug template for effective treatment of invasive ductal breast carcinoma and its bone metastasis as well as new therapeutic perspective for drug design.
authors.affiliation: Bozok University, Faculty of Arts and Sciences, Department of Chemistry, Yozgat, Turkey. Electronic address: i_koca@yahoo.com.
authors.forename: İrfan
authors.initials: İ
authors.lastname: Koca
authors.affiliation: Gaziosmanpaşa University, Faculty of Natural Sciences and Engineering, Department of Bioengineering, Tokat, Turkey.
authors.forename: Aykut
authors.initials: A
authors.lastname: Özgür
authors.affiliation: Bozok University, Faculty of Arts and Sciences, Department of Chemistry, Yozgat, Turkey.
authors.forename: Muhammet
authors.initials: M
authors.lastname: Er
authors.affiliation: Bozok University, Faculty of Arts and Sciences, Department of Chemistry, Yozgat, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gümüş
authors.affiliation: Gaziosmanpaşa University, Faculty of Natural Sciences and Engineering, Department of Bioengineering, Tokat, Turkey.
authors.forename: Kübra
authors.initials: K
authors.lastname: Açikalin Coşkun
authors.affiliation: Cumhuriyet University, Faculty of Pharmacy, Department of Basic Sciences, Division of Biochemistry, Sivas, Turkey. Electronic address: ytutar@cumhuriyet.edu.tr.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Tutar
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D062105:Molecular Docking Simulation; D000072757:Protein Conformation, beta-Strand; D013890:Thiourea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D013890:Thiourea
keywords: Bone cancer; Breast cancer; Client proteins; Hsp90; Pyrimidine; Thiourea