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Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents
- Source :
- European Journal of Medicinal Chemistry. 110:164-180
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction.
- Subjects :
- Male
Curcumin
Cell cycle checkpoint
Uterine Cervical Neoplasms
Antineoplastic Agents
Pharmacology
Trientine
01 natural sciences
Article
HeLa
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Prostate cancer
0302 clinical medicine
Cell Line, Tumor
Neoplasms
Drug Discovery
medicine
Humans
Structure–activity relationship
Cytotoxicity
Cell Proliferation
biology
010405 organic chemistry
Cell growth
Organic Chemistry
Prostatic Neoplasms
General Medicine
medicine.disease
biology.organism_classification
0104 chemical sciences
chemistry
Apoptosis
Drug Design
030220 oncology & carcinogenesis
Female
Drug Screening Assays, Antitumor
HeLa Cells
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 110
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....00b67db95bfdafe8e7a2f4360b0bc12e