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    Acyl Thiourea Derivatives Containing Pyrazole Ring Selective Targeting of Human Aurora Kinases in Breast and Bone Cancer
    (BENTHAM SCIENCE PUBL LTD, 2015) Ozgur, Aykut; Yenidunya, Eren; Koca, Irfan; Tutar, Yusuf
    Several oncogenic pathways may lead to cancer. Pharmaceutical research develops efficacious compounds to inhibit these pathways. Current inhibitor drugs may block several pathways simultaneously but cause adverse and side effects. Therefore, we designed novel acyl thiourea derivatives containing pyrazole ring to selectively inhibit a kinase dependent pathway in cancer. In this study, breast and bone cancer cells were employed to monitor this selectivity. Since metastatic breast cancer spreads to bone, MCF-7 along with epithelial (Saos-2) and fibroblast (MG-63) human bone cancer cell lines were used to observe inhibitory effects of the synthesized compounds. It has been reported that Estrogen receptor alpha (ER-alpha) and Aurora kinase A and B are involved in different pathways at breast and bone cancer mechanism. Synthesized novel inhibitors presented in this work effectively and selectively bind to Aurora kinase A and B but do not interact with ER-alpha however; a generic inhibitor PHA-739358 binds to all three enzymes. This improved binding mode of the novel inhibitors may be a useful therapeutic strategy for the treatment of breast and bone cancer approaches and provides potency to personalized medicine.
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    Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2016) Koca, Irfan; Ozgur, Aykut; Er, Muhammet; Gumus, Mehmet; Coskun, Kubra Acikalin; Tutar, Yusuf
    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 mu M 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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    Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis
    (BENTHAM SCIENCE PUBL LTD, 2016) Gumus, Mehmet; Ozgur, Aykut; Tutar, Lutfi; Disli, Ali; Koca, Irfan; Tutar, Yusuf
    Background: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor. Methods: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity. Results: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 mu M and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways. Conclusion: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.
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    Designing Specific HSP70 Substrate Binding Domain Inhibitor for Perturbing Protein Folding Pathways to Inhibit Cancer Mechanism
    (Bentham Science Publ Ltd, 2021) Coskun, Kubra A.; Koca, Irfan; Gumus, Mehmet; Tutar, Yusuf
    Background: HSP70 is a survival factor for tumor cells in transformation and in tumor progression as well as in anti-apoptotic response. Objective: Several inhibitors targeting HSP70 ATPase function displayed off-target effects, but PES, which targets the HSP70 substrate binding domain, prevents tumor cell survival prominently. However, PES may not bind HSP70 in the absence of nucleotide. This research aimed to design a unique inhibitor molecule that works both in the presence and absence of nucleotides to amplify inhibition. Methods: A set of chimeric coumarine-pyrazole derivatives were determined by in silico techniques and synthesized to elucidate their inhibitory effects. Cell viability experiments displayed KBR1307 as the most efficient inhibitor. A set of characterization experiments were performed, and the results were compared to that of PES agent. Binding constant, ATP hydrolysis rate, and percent aggregation were determined in the presence and absence of inhibitors. Results: In silico docking experiments showed that only KBR1307 binds the HSP70 substrate binding domain and interacts with cochaperone interface. Binding experiments indicated that KBR1307 binds HSP70 both in the presence and absence of nucleotides, but PES does not. Both inhibitors significantly lower HSP70 ATPase activity and substrate protein disaggregation activity. However, KBR1307 displays a lower IC50 value at the MCF-7 cell line compared to PES. Both inhibitors do not alter HSP70 secondary structure composition and overall stability. Conclusion: KBR1307 effectively inhibits HSP70 compared to PES and provides a promising template for novel anticancer drug development.
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    A Novel Approach to Inhibit Heat Shock Response as Anticancer Strategy by Coumarine Compounds Containing Thiazole Skeleton
    (BENTHAM SCIENCE PUBL LTD, 2015) Koca, Irfan; Gumus, Mehmet; Ozgur, Aykut; Disli, Ali; Tutar, Yusuf
    Inhibition of the Hsp90 function is an essential therapeutic approach and several inhibitors were designed as anti-cancer agents. These inhibitors are ATPases and they aim to deregulate Hsp90 folding function. ATPase proteins are common in human metabolism but they form nonspecific targets. Hsp90 functions as dimer with coordinating chaperones. Heat Shock Organizing Protein (Hop) forms a bridge between Hsp90 and Hsp70-Hsp40 complex to form Hsp90-Hsp70 coordination. Perturbing conformational changes of these Hsp proteins, dimer formation, and protein-protein interactions inhibit Hsp90 substrate protein folding function. This approach does not target all ATPase proteins but targets Hsp90 function solely. For this purpose, we designed compounds to block Hsp90 function. Moreover, molecular docking studies as well as competition analysis of the compounds were performed with Hsp90. Novel thiazolyl coumarine compounds were determined as valuable C-terminal Hsp90 inhibitors and provide promising templates for the drug design. Anticancer activities of these novel compounds were tested by employing human colon (DLD-1) and liver cancer (HepG2) cell lines. Thiazolyl coumarine compounds are found to be significant and useful for the treatment of human colon and liver cancer as evidenced by in vitro and in silico results.
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    Pyrazolyl-Benzoxazinone Derivatives as Dual Hsp Inhibitors in Human Breast Cancer
    (Wiley-V C H Verlag Gmbh, 2022) Koca, Irfan; Kamaci, Volkan; Ozsoy, Ceylan; Sert, Yusuf; Kani, Ibrahim; Tutar, Lutfi; Tutar, Yusuf
    Heat Shock Proteins (Hsps) play major role on the onset of several cancers. Metabolic rates of cancer cells are higher compared to that of untransformed cells. This accelerated rate force functional substrate proteins to fold faster than normal folding rate. Although, the process leads cell cycle halting and eventually induces apoptosis, Hsps help cell survival and inhibit apoptosis and fold substrate proteins especially signaling proteins. When cancer cells accelerate the metabolism for invasion and metastasis, substrate proteins must fold to their native state rapidly. Since, functional forms of the proteins must be folded properly, cancer cells overexpress Hsps to fold substrate proteins and avoid apoptosis. Hsp90 and Hsp70 play key role in these processes. Inhibition of either Hsp90 or Hsp70 display complementary function. Therefore, dual inhibition of Hsp70 and Hsp90 potentially provides anticancer affect. In silico studies showed that pyrazolyl-benzoxazine derivatives display binding activity for both Hsps. For this purpose, pyrazole-3-carbonyl chloride were converted to pyrazolyl-benzoxazine derivatives via reactions of anthranilic acids in good yields (68-83 %). The structures of the newly synthesized compounds were elucidated by IR-NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. Binding of the compounds inhibit function of Hsps and cause cytotoxic effect over MCF-7 cells. The compounds display potential anticancer effects.
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    Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety
    (PERGAMON-ELSEVIER SCIENCE LTD, 2013) Koca, Irfan; Ozgur, Aykut; Coskun, Kubra Acikalin; Tutar, Yusuf
    In this work novel organic based compounds, acyl thiourea derivatives were synthesized and their anticancer activities were investigated. A new series of acyl thiourea derivatives containing pyrazole ring were prepared in good yield through one pot reaction of 4-benzoyl-1, 5-diphenyl-1H-pyrazole-3-carbonyl chloride with ammonium thiocyanate and various amines. The structures of the newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR and elemental analysis. Anticancer activities of synthesized compounds were evaluated on human colon, liver and leukemia cancer cell lines. Cell culture studies have demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity have altered in the presence of various side groups. These results confirm that novel pyrazolyl acyl thioureas derived compounds may be utilized for cancer treatment. Furthermore, these compounds have a great potential and significance for further investigations. (C)2013 Elsevier Ltd. All rights reserved.