Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl- imidazole derivatives targeting tubulin polymerization

Jianjun Chen, Chien Ming Li, Jin Wang, Sunjoo Ahn, Zhao Wang, Yan Lu, James T. Dalton, Duane Miller, Wei Li

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure-activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency.

Original languageEnglish (US)
Pages (from-to)4782-4795
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number16
DOIs
StatePublished - Aug 15 2011

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Structure-Activity Relationship
Tubulin
Polymerization
Cells
Paclitaxel
Derivatives
Cell Line
Melanoma
Imidazoles
Methylation
Liver Microsomes
Metabolic Networks and Pathways
Scaffolds
Liver
Rats
Tumors
Neoplasms
Prostatic Neoplasms
Ligands
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl- imidazole derivatives targeting tubulin polymerization. / Chen, Jianjun; Li, Chien Ming; Wang, Jin; Ahn, Sunjoo; Wang, Zhao; Lu, Yan; Dalton, James T.; Miller, Duane; Li, Wei.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 16, 15.08.2011, p. 4782-4795.

Research output: Contribution to journalArticle

Chen, Jianjun ; Li, Chien Ming ; Wang, Jin ; Ahn, Sunjoo ; Wang, Zhao ; Lu, Yan ; Dalton, James T. ; Miller, Duane ; Li, Wei. / Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl- imidazole derivatives targeting tubulin polymerization. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 16. pp. 4782-4795.
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