Synthesis and Anticancer Properties of New 3-Methylidene-1-sulfonyl-2,3-dihydroquinolin-4(1H)-ones

Abstract

Quinolinones have been known for a long time as broad-spectrum synthetic antibiotics. More recently, the anticancer potential of this group of compounds has been investigated. Following this direction, we obtained a small library of 3-methylidene-1-sulfonyl-2,3-dihydroquinolin-4(1H)-ones with various substituents at positions 1, 2, 6, and 7 of the quinolinone ring system. The cytotoxic activity of the synthesized analogs was tested in the MTT assay on two cancer cell lines in order to determine the structure–activity relationship. All compounds produced high cytotoxic effects in MCF-7, and even higher in HL-60 cells. 2-Ethyl-3-methylidene-1-phenylsulfonyl-2,3-dihydroquinolin-4(1H)-one, which was over 5-fold more cytotoxic for HL-60 than for normal HUVEC cells, was selected for further tests. This analog was shown to inhibit proliferation and induce DNA damage and apoptosis in HL-60 cells.

Synthesis And Anticancer Activity Of New Hybrid 3‐Methylidene‐2,3‐Dihydro‐1,8‐Naphthyridinones

“…In turn, enol forms showed singlets or doublets of the proton of hydroxyl group with chemical shifts in the range of 10.97–11.33 ppm and 4 J H‐P =0.9–1.1 Hz. Similar differences between 3 J H2‐H3 coupling constants were found in the structurally related cis ‐ and trans ‐3‐diethoxyphosphoryl‐2,3‐dihydroquinolin‐4(1 H )‐ones 3 , recently synthesized in our laboratory [6,7] .…”

“…In turn, enol forms showed singlets or doublets of the proton of hydroxyl group with chemical shifts in the range of 10.97-11.33 ppm and 4 J H-P = 0.9-1.1 Hz. Similar differences between 3 J H2-H3 coupling constants were found in the structurally related cis-and trans-3-diethoxyphosphoryl-2,3-dihydroquinolin-4(1H)ones 3, recently synthesized in our laboratory [6,7] . With phosphonates 9 a-p in hand we proceeded with their transformation into target 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones 4, applying conditions which were effective for the synthesis of 3-methylidene-1-sulfonyl-2,3dihydroquinolin-4(1H)-ones 3 [6,7] .…”

“…The target compounds were synthesized by applying a modified methodology originally reported for the synthesis of 3-methylidene-1-tosyl-2,3-dihydroquinolin-4(1H)-ones 3 [6,7] . The four step reaction sequence starts with methyl 2-aminonicotinate 5 which undergoes N-sulfonylation reaction with tosyl chloride in pyridine to give N-tosylnicotinate 6 in 61 % yield (Scheme 1).…”

“…The four step reaction sequence starts with methyl 2-aminonicotinate 5 which undergoes N-sulfonylation reaction with tosyl chloride in pyridine to give N-tosylnicotinate 6 in 61 % yield (Scheme 1). Acylation of diethyl methylphosphonate (7) with Ntosylnicotinate 6 in the presence of three equivalents of lithium diisopropylamide (LDA) gave diethyl 2-oxo-2-(2-tosylaminopyridin-3-yl)ethylphosphonate ( 8) in 77 % yield. In the next step condensation of 8 with various alkyl or aryl aldehydes, followed by spontaneous intramolecular aza-Michael addition, was performed.…”

“…In the search for novel anticancer agents, we recently synthesized a series of 3-methylidene-2,3-dihydroquinolin-4(1H)-ones 3 with various substituents in the positions 1, 2, 6 and 7 [6,7] . The cytotoxic activities of these compounds were assessed against two cancer cell lines, promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7.…”