Synthesis and Biological Evaluation of Aryloxazole Derivatives as Antimitotic and Vascular-Disrupting Agents for Cancer Therapy

A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umb...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (22), p.9008-9018
Main Authors: Choi, Min Jeong, No, Eun Sun, Thorat, Dhanaji Achyutrao, Jang, Jae Wan, Yang, Hakkyun, Lee, Jaeick, Choo, Hyunah, Kim, Soo Jin, Lee, Chang Sik, Ko, Soo Young, Lee, Jiyoun, Nam, GhilSoo, Pae, Ae Nim
Format: Article
Language:English
Subjects:
Animals
Antimitotic Agents - chemical synthesis
Antimitotic Agents - chemistry
Antimitotic Agents - metabolism
Antimitotic Agents - pharmacology
Blood Vessels - drug effects
Cell Proliferation - drug effects
Chemistry Techniques, Synthetic
Drug Stability
HL-60 Cells
Human Umbilical Vein Endothelial Cells - drug effects
Humans
Male
Mice
Mice, Inbred BALB C
Microsomes, Liver - metabolism
Models, Molecular
Oxazoles - chemical synthesis
Oxazoles - chemistry
Oxazoles - metabolism
Oxazoles - pharmacology
Protein Multimerization - drug effects
Protein Structure, Quaternary
Structure-Activity Relationship
Tubulin - chemistry
Xenograft Model Antitumor Assays
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Summary:A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (6-48 and 6-51) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound 6-48 effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound 6-48 will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm400840p