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Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1 H )‐ones as Potent Cytotoxic Agents
Author(s) -
Koszuk Jacek,
Bartosik Tomasz,
Wojciechowski Jakub,
Wolf Wojciech M.,
Janecka Anna,
Drogosz Joanna,
Długosz Angelika,
Krajewska Urszula,
Mirowski Marek,
Janecki Tomasz
Publication year - 2018
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201800242
Subject(s) - chemistry , cytotoxic t cell , cell culture , stereochemistry , cancer cell , reagent , cancer , combinatorial chemistry , biochemistry , organic chemistry , medicine , biology , genetics , in vitro
An efficient synthetic strategy to 3‐methylidene‐2,3‐dihydroquinolin‐4(1 H )‐ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2‐(tosylamino)benzoate, condensation of thus formed diethyl 2‐oxo‐2‐(2‐ N ‐tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3‐(diethoxyphosphoryl)‐1,2‐dihydroquinolin‐4‐ols as Horner–Wadsworth–Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3‐dimenthoxyphosphoryl group as a chiral auxiliary. Single X‐ray crystal analysis of (2 S )‐3‐(dimenthoxyphosphoryl)‐2‐phenyl‐1‐tosyldihydroquinolin‐4‐ol revealed the presence of strong resonance‐assisted hydrogen bond ( RAHB ). The obtained 3‐methylidene‐2,3‐dihydroquinolin‐4(1 H )‐ones were then tested for their cytotoxic activity against two leukemia cell lines NALM ‐6 and HL ‐60 and a breast cancer MCF ‐7 cell line. All compounds showed very high cytotoxic activity with the IC 50 values mostly below 1 μ m in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells ( HUVEC ) and on human mammary gland/breast cells ( MCF ‐10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB 1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF ‐7 cells treated with two selected analogs. Both compounds were strong ABCB 1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.