Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

• Published in: Chemistry & biodiversity 2018-09, Vol.15 (9), p.e1800242-n/a
• Main Authors: Koszuk, Jacek, Bartosik, Tomasz, Wojciechowski, Jakub, Wolf, Wojciech M., Janecka, Anna, Drogosz, Joanna, Długosz, Angelika, Krajewska, Urszula, Mirowski, Marek, Janecki, Tomasz
• Format: Article
• Language: English
• Subjects: 3‐methylidenequinolin‐4‐ones; ABCB1 transporter inhibitors; Aldehydes; Analogs; Antineoplastic drugs; Antitumor agents; Biotechnology; Breast cancer; Cancer; Chemical synthesis; Chemotherapy; Cytotoxic agents; cytotoxic evaluation; Cytotoxicity; Drug resistance; Efflux; Enantiomers; Endothelial cells; Horner–Wadsworth–Emmons olefination; Hydrogen bonds; Leukemia; Mammary gland; Mammary glands; mRNA; Reagents; Resistance factors; resonance‐assisted hydrogen bond; Tumor cell lines; Umbilical vein
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201800242

An efficient synthetic strategy to 3‐methylidene‐2,3‐dihydroquinolin‐4(1H)‐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 (2S)‐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(1H)‐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 IC50 values mostly below 1 μm 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 ABCB1 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 ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.