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Structure–Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents
- Source :
- Journal of Medicinal Chemistry. 58:4713-4726
- Publication Year :
- 2015
- Publisher :
- American Chemical Society (ACS), 2015.
-
Abstract
- Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles.
- Subjects :
- Male
Models, Molecular
Curcumin
Stereochemistry
Uterine Cervical Neoplasms
Antineoplastic Agents
Article
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Tandem Mass Spectrometry
Prostate
Pentanones
Drug Discovery
Tumor Cells, Cultured
medicine
Animals
Humans
Potency
Structure–activity relationship
Tissue Distribution
Cytotoxicity
Chromatography, High Pressure Liquid
Cell Proliferation
Trifluoromethyl
Molecular Structure
Chemistry
Prostatic Neoplasms
In vitro
Mice, Inbred C57BL
Thiazoles
medicine.anatomical_structure
Drug Design
Molecular Medicine
Female
Linker
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....fdc65ddecd8ad0bca84a58687c50bfb6