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

Abstract

Background: From a chemistry point of view, we hypothesized that superlative dual cytotoxicity-radical scavenging bioefficacies of series 4 FQs correlate to their acidic groups and C8-C7 ethylene diamine Chelation Bridge.

Methodology: Newly synthesized 16 lipophilic-acid chelating FQs have been screened for in vitro duality of proliferation inhibition and radical scavenging capacities.

Results: Substantially in LPS prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of new FQs' NO scavenging/antiinflammation capacity were 4e<4b<3d<4f<5c0.05). In comparison to classical and robust antineoplastic agent cisplatin and unlike triazoloFQs; nitroFQs (3a, 3b and 3f) and the reduced FQs (4a, 4c, 4d and 4e) exerted antiproliferation IC50 values <50 µM in leukaemia K562. Besides nitroFQ 3, the reduced FQs (4c and 4f) exhibited antineoplastic IC50 values <50 µM in lung A549 carcinoma. NitroFQ 3c and reduced FQs 4b, 4c, and 4f in breast MCF7 and reduced 4c in pancreatic PANC1 had reduction of viability IC50 values <50 µM. NitroFQ 3e, reduced FQs 4b and, 4c and triazoloFQ 5a exerted antiproliferation IC50 values <50 µM in breast T47D cells. Also nitroFQ 3e, reduced FQ 4c and triazoloFQ 5f exhibited antineoplastic IC50 values <50 µM in PC3 prostate cancer cells. Exceptionally triazoloFQ 5a, but neither nitro- nor reduced FQs, had cytotoxicity IC50 value <50 µM in resistant melanoma A375 cells. Unequivocally 4b antineoplastic effectiveness linked with its radical scavenging and antiinflammation effects while 3d and 5c lacked matching antiproliferation potentialities to their exquisite antiinflammation capacities. Explicitly reduced 4e and 4f exerted antiinflammation-selective cytotoxicity duality in vitro.

Conclusion: Collectively, this work reveals lipophilic-acidic chelator FQs as authentic agents for the repurposing approach in anticancer chemotherapy/prevention.

Keywords: Antiinflammation and antiCancer; Cisplatin; Fluoroquinolones and Triazoloquinolones; NO-radical scavenging; Sulphorodhamine B and Greiss assay.

Chart 1

Target FQs with more Lipophilic

Figure 1

Order of Activity Based on the Structural Scaffold in a Strong Group against K562

Chart 2

Representative FQs Drugs

Figure 2

4''-methoxy Substitution Effect on Activity K562

Figure 3

Possible Effects that Explain the Weak Activity of 4a

Figure 4

Effect of Methoxy Substitution in 4c and 4a against All Cell Lines Tested

Figure 5

C-8 Amino Group in 4c

Figure 6a

Contribution of C-8 Amino Group (4 series) in Anti-Proliferative Activity; A- H-B; B-Chelating agents, C-Antioxidant and D- 1,8-bridging (rigidity)

Figure 6b

Chelator Groups Shared by All Anti Proliferating FQs and Doxorubicin