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Title: Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety

Abstract

In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 µM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors.

Authors:
 [1];  [2];  [3];  [1];  [1];  [4];  [5];  [6];  [5];  [1]
  1. Anadolu Univ., Eskisehir (Turkey). Dept. of Pharmaceutical Chemistry. Faculty of Pharmacy
  2. Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford PULSE Inst.
  3. Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; National Research Center, Cairo (Egypt). Dept. of Chemistry of Natural Compounds
  4. Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; Minia Univ. (Egypt). Dept. of Medicinal Chemistry
  5. Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy
  6. Kumamoto Univ. (Japan). Research Inst. for Drug Discovery. School of Pharmacy
Publication Date:
Research Org.:
Anadolu Univ., Eskisehir (Turkey); Kumamoto Univ. (Japan); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE; Anadolu Univ. Scientific Research Projects Commission (Turkey); Japanese Society for the Promotion of Science (JSPS)
OSTI Identifier:
1425396
Grant/Contract Number:  
AC02-76SF00515; 1605S198; 16039901-000867
Resource Type:
Accepted Manuscript
Journal Name:
Molecules
Additional Journal Information:
Journal Volume: 23; Journal Issue: 1; Journal ID: ISSN 1420-3049
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; thiadiazole; thiazole; benzothiazole; Bcr-Abl; kinase inhibitor; leukemia

Citation Formats

Altıntop, Mehlika, Ciftci, Halil, Radwan, Mohamed, Sever, Belgin, Kaplancıklı, Zafer, Ali, Taha, Koga, Ryoko, Fujita, Mikako, Otsuka, Masami, and Özdemir, Ahmet. Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety. United States: N. p., 2017. Web. doi:10.3390/molecules23010059.
Altıntop, Mehlika, Ciftci, Halil, Radwan, Mohamed, Sever, Belgin, Kaplancıklı, Zafer, Ali, Taha, Koga, Ryoko, Fujita, Mikako, Otsuka, Masami, & Özdemir, Ahmet. Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety. United States. doi:10.3390/molecules23010059.
Altıntop, Mehlika, Ciftci, Halil, Radwan, Mohamed, Sever, Belgin, Kaplancıklı, Zafer, Ali, Taha, Koga, Ryoko, Fujita, Mikako, Otsuka, Masami, and Özdemir, Ahmet. Wed . "Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety". United States. doi:10.3390/molecules23010059. https://www.osti.gov/servlets/purl/1425396.
@article{osti_1425396,
title = {Design, Synthesis, and Biological Evaluation of Novel 1,3,4-Thiadiazole Derivatives as Potential Antitumor Agents against Chronic Myelogenous Leukemia: Striking Effect of Nitrothiazole Moiety},
author = {Altıntop, Mehlika and Ciftci, Halil and Radwan, Mohamed and Sever, Belgin and Kaplancıklı, Zafer and Ali, Taha and Koga, Ryoko and Fujita, Mikako and Otsuka, Masami and Özdemir, Ahmet},
abstractNote = {In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 µM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors.},
doi = {10.3390/molecules23010059},
journal = {Molecules},
number = 1,
volume = 23,
place = {United States},
year = {2017},
month = {12}
}

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