Antiproliferative Activities of Lipophililic Fluoroquinolones- Based Scaffold Against a Panel of Solid and Liquid Cancer Cell Lines

Abstract

Objectives: In this work, 9 lipophilic-acid chelating FQs (fluoroquinolones) comprising chelating groups have been prepared, characterized and screened for in vitro cytotoxicity, radical scavenging and antiinflammation propensities. Methods: Using sulforhodamine B colorimetric bioassay vs. cisplatin; FQs-inflicted reductions' of viability against breast T47D and MCF7, Pancreatic PANC-1, colorectal HT29, HCT116, SW620, CACO2, SW480 and Leukaemia K562 cancer cell lines were examined in quadruplicates/dose/cell line. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH-and NO-radicals' scavenging capacities -as their molecular action mechanism-in comparison to ascorbic acid and indomethacin respectively. Using Griess assay in Lipopolysaccharide (LPS) prompted RAW264.7 macrophages; mitigation of inflammation was investigated. Results: nitroFQ 3b, unlike the rest of FQs in PANC1 and MCF7 cells, exhibited remarkably superior NO-radical scavenging/ antiinflammation capacity to indomethacin with respective antiproliferative IC 50 values (<50µM) 49 vs. cisplatin's 122 and 6 vs. cisplatin's 28 (p<0.01-0.001; n=4). Reduced FQ 4b of significantly dual DPPH-NO scavenging propensities exerted exceptionally substantial micromolar antiproliferation in colorectal cancer cells with respective antiproliferative IC 50 values (<50µM) of HCT116 0.84< HT29 1.6<PANC1 5.7<SW620 9.2 vs. cisplatins', (p<0.01-0.001; n=4). FQ 5a of superb NO radical reduction effect had antiproliferative IC 50 value (<50µM) of 37.6 in PANC1 cells. In breast cancer T47D the ascending order of pronounced nano-micromolar antiproliferative IC 50 values (<50µM) was 4d<3d<4a<4b<3b (0.009<0.59<10<15<41 vs. cisplatins', p<0.01-0.001; n=4). Both 4d and 4b displayed both DPPH-NO radicals reduction -related cytotoxicities. NO radical scavengers 3d and 3b as well as DPPH radical scavenger 4a exerted highly appreciably relevant antineoplastic affinities. Conclusion: Acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations can be substantially associated with molecular action mechanisms of FQs cytotoxicities, antioxidative and antiinflammation effects, collectively.

Selected Statins as Dual Antiproliferative-Antiinflammatory Compounds

“…These data were further validated with other cell lines including colorectal cancer (CRC); fortifying the fact that atorvastatin has an apoptotic effect on cancer cells, particularly colorectal (CRC) and BC (in SW620 cells with IC 50 value accounting to 0.0018 ±0000 µM) and accordingly high safety (Mamdooh et al, 2019). This foundation furnished for this work basically constructed for elucidation of possible molecular antineoplastic action mechanism via antiinflammation (Hallaq et al, 2022;Khaleel et al, 2022;Qashou et al, 2022;Salih et al, 2022).…”

“…The mechanism of reduction of cell viability was adopted as described previously (Vichai and Kirtikara, 2006). As a robust and classical antineoplastic apoptogenic reference agent (El-Hamoly et al, 2017), cisplatin (1-200 μM) was recruited for comparison purposes (Alabsi et al, 2018;Mamdooh et al, 2019;AlKhalil et al, 2020;Hallaq et al, 2022;Khaleel et al, 2022;Qashou et al, 2022;Salih et al, 2022). Dose-response curves were plotted and values were expressed as percentage of control optical density and IC 50 values 50% inhibitory concentration were estimated by regression analysis (Papazisis et al, 1997).…”

“…Selectivity index (SI) is the term that describes the safety of tested drugs. It is calculated by dividing IC 50 value of tested compound on fibroblasts by the least IC 50 value of the same compound on any specific pathological cell line (Hoffmann, et al, 2011;Hallaq et al, 2022;Khaleel et al, 2022;Qashou et al, 2022;Salih et al, 2022).…”

“…Ascorbic acid was the robust and classical standard radical scavenging reference agent for comparison purposes. The calculation of the DPPH radical scavenging activity inhibition was determined by the following equation where A represents photometric absorbance: in % = (A control -A sample) / A control x 100% (Litwinienko and Ingold, 2004;Sharma and Bhat, 2009;Marinova and Batchvarov, 2011;Shalaby and Shanab, 2013;Karahan et al, 2015;Hidayat, et al, 2017;Haida, 2019;Paulpriya et al, 2015;Shen et al, 2010;Hallaq et al, 2022;Khaleel et al, 2022;Qashou et al, 2022;Salih et al, 2022).…”

Newly Substituted Anilino-Fluoroquinolones with Proliferation Inhibition Potential against a Panel of Cancer Cell Lines

“…Vosaroxin is a commercial fluoroquinolone (FQ) with antineoplastic propensities in acute myeloid leukemia comparable to anticancer agents doxorubicin and cisplatin (Bruno et al, 2020). Newly developed synthetic chelator Fluoroquinolones (FQs) had the scaffold for FQs but carried extra lipophilic and chelator groups as structural functionalities for optimal cytotoxicities similar to doxorubicin (Arabiyat, et al, 2016a,b;Khaleel et al, 2021;AlHallaq et al, 2022;Qashou et al, 2022). Our hypothesis was based to dual lipophilic-acidic chelating FQs with a genuine potential of antiproliferative propensities based to their dual DPPH-and NO-radicals scavenging biocapacities using cell based -and colorimetric assays vs. respective reference agents as their molecular action mechanism.…”