Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents

A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles ( 6a– u) has been discovered as potent Abl tyrosine kinase inhibitors showing an interesting inhibitory activity on murine myeloid 3B clone and drug resistant subclones. A series of substituted benzoylamino-2-[(4-benzyl)thio]...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-02, Vol.18 (3), p.1207-1211
Main Authors: Radi, Marco, Crespan, Emmanuele, Botta, Giorgia, Falchi, Federico, Maga, Giovanni, Manetti, Fabrizio, Corradi, Valentina, Mancini, Manuela, Santucci, Maria Alessandra, Schenone, Silvia, Botta, Maurizio
Format: Article
Language:English
Subjects:
1,3,4-Thiadiazoles
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Bcr-Abl
Biological and medical sciences
General aspects
Humans
Leukemia
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-abl - antagonists & inhibitors
SAR
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Thiadiazoles - chemical synthesis
Thiadiazoles - chemistry
Thiadiazoles - pharmacology
Tyrosine kinase inhibitors
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Summary:A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles ( 6a– u) has been discovered as potent Abl tyrosine kinase inhibitors showing an interesting inhibitory activity on murine myeloid 3B clone and drug resistant subclones. A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles has been discovered as potent Abl tyrosine kinase inhibitors. Molecular docking simulations on the Abl tyrosine kinase were conducted in order to rationalize the SAR of the synthesized inhibitors. The most active compound identified from the enzymatic screening ( 6a) showed interesting inhibitory activity on Imatinib-sensitive murine myeloid 3B clone and Bcr-Abl-independent Imatinib-resistant leukemia cells. Surprisingly, 6a was also proved to act as differentiating inducers in human promyelocytic leukemia cells (HL-60).
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2007.11.112