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

Altıntop, Mehlika; Ciftci, Halil; Radwan, Mohamed; Sever, Belgin; Kaplancıklı, Zafer; Ali, Taha; Koga, Ryoko; Fujita, Mikako; Otsuka, Masami; Özdemir, Ahmet

doi:10.3390/molecules23010059

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

Journal Article · Wed Dec 27 00:00:00 EST 2017 · Molecules

DOI:https://doi.org/10.3390/molecules23010059· OSTI ID:1425396

Altıntop, Mehlika ^[1]; Ciftci, Halil ^[2]; Radwan, Mohamed ^[3]; Sever, Belgin ^[1]; Kaplancıklı, Zafer ^[1]; Ali, Taha ^[4]; Koga, Ryoko ^[5]; Fujita, Mikako ^[6]; Otsuka, Masami ^[5]; Özdemir, Ahmet ^[1]

Anadolu Univ., Eskisehir (Turkey). Dept. of Pharmaceutical Chemistry. Faculty of Pharmacy
Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford PULSE Inst.
Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; National Research Center, Cairo (Egypt). Dept. of Chemistry of Natural Compounds
Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy; Minia Univ. (Egypt). Dept. of Medicinal Chemistry
Kumamoto Univ. (Japan). Dept. of Bioorganic Medicinal Chemistry. School of Pharmacy
Kumamoto Univ. (Japan). Research Inst. for Drug Discovery. School of Pharmacy

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.

View Accepted Manuscript (DOE)

Research Organization:: Anadolu Univ., Eskisehir (Turkey); Kumamoto Univ. (Japan); SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: Anadolu Univ. Scientific Research Projects Commission (Turkey); Japanese Society for the Promotion of Science (JSPS); USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1425396

Journal Information:: Molecules, Journal Name: Molecules Journal Issue: 1 Vol. 23; ISSN 1420-3049

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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Bcr-Abl
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thiadiazole
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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

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