Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities

Abstract

Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Nitrones can release nitric oxide in larger amounts compared to corresponding oximes. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines. Compounds 6c, 6e, and 6f exhibited higher potency as anticancer agents compared to doxorubicin, with IC 50 ranging from 0.45 to 0.91 μM. A remarkable overexpression of caspase-3 protein levels was observed in cells treated with the tested compounds. Compound 6e exhibited more pre-G1 apoptosis and cell cycle arrest at the G2/M phase than in other phases.These results revealed that the tested compounds can cause programmed cell death through overexpression of caspase 3, which may be attributed to the release of nitric oxide. K E Y W O R D S antiproliferative, apoptosis, caspase 3, nitric oxide, nitrones, oximes 1 | INTRODUCTION Quinoline is a significant nucleus which has attracted the attention of medicinal chemists due to its variable pharmacological activities. Easy functionalization of various ring positions of quinoline makes it an attractive synthetic building block for design and synthesis of new drugs. Additionally, quinolines are considered as an interesting group of compounds, many of which have widespread pharmacologicalactions such as anti-microbial, [1][2][3][4] anti-inflammatory, [5][6][7][8] antitubercular, [9][10][11][12] anti-convulsant, [13] antihypertensive, [14,15] antioxidant, [16][17][18][19] and anticancer [20] activities. Several mechanisms can explain the anticancer effect of quinoline derivatives including: topoisomerase inhibition, [21][22][23] DNA intercalation, [24] protein kinases inhibition, [25][26][27] tubulin polymerase inhibition, [28][29][30][31] and induction of apoptosis. [32,33] Quinoline derivative I exhibited potent anticancer activity against brain cancer cell line U87 with IC 50 of 1.5 nM. [31] Compound II exhibits remarkable anticancer activity against HL60 cancer cell line with IC 50 of 0.68 μM (Figure 1). [33] Incorporation of biologically active moieties into quinoline such as nitrones [34] and oximes [35] may produce biologically active anticancer agents.Compound III showed significant anticancer activity with IC 50 of 31.42 μM against Hep-G 2 cancer cell line (Figure 1). [34] Nitrones are a Arch Pharm Chem Life Sci. 2019;352:e1800270.wileyonlinelibrary.com/journal/ardp

Expression of Concern: Preventive effect of nerolidol on isoproterenol induced myocardial damage in Wistar rats: Evidences from biochemical and histopathological studies

“…It inhibits lipid peroxidation by protecting myocardial membranes and inhibiting the membrane peroxidative damage and atherogenesis (Upston, Terentis, & Stocker, ). In the present study, the above nonenzymatic antioxidants such as vitamin C, vitamin E, and GSH were significantly reduced in ISO administered rats and our results are in concord with formerly reported investigations (Abdelbaset et al, ). NRD pretreated rats restored the levels of vitamin C, vitamin E, and GSH in both plasma and heart of ISO rats when compared with ISO alone treated rats.…”

Design, Synthesis, Molecular Docking, Antiapoptotic and Caspase-3 Inhibition of New 1,2,3-Triazole/Bis-2(1H)-Quinolinone Hybrids

“…For more proof of caspase-3 inhibition by our synthesized compounds, cell-based cytochrome C was assayed. It was reported that cytochrome C concentration in the cell has a critical role in the inactivation of caspases and prohibiting the intrinsic apoptosis pathway [ 57 ]. Antiapoptotic proteins can inhibit apoptosis by blocking the release of cytochrome C while proapoptotic members function as activators of its release.…”

“…Cells were collected from American Type Culture Collection to be grown in SR containing 10% fetal bovine serum at 37 °C, stimulated with the compounds to be tested for cytochrome C using Cytochrome C Human ELISA Kit (ab119521—Cytochrome C Human ELISA Kit, Vaccera institute, Egypt) [ 57 ] (See Supplementary Materials ).…”

Report on Recently (2017–20) Designed Quinoline‐Based Human Cancer Cell Growth Inhibitors

“…Novel quinoline derivatives bearing nitrone or oxime nitric oxide donors are designed. [97] Firstly, all the compounds including starting material, intermediates, and nitrone analogs were investigated for NO releasing ability. Based on results of this activity, quinoline nitrone derivatives were chosen for exploration of antiproliferative effects.…”

“…Sulfur and Silicon containing anticancer quinoline molecules B. [95][96][97][98][99] potent MCF-7 inhibitory properties with IC 50 values of 38.…”