Synthesis, Biological Assay, and SAR of Potential Anticancer Lipophilic Fluoroquinolones (FQs) and Pyridoquinoxalines (PQs) Conjugated to Gold Nanoparticles for Synergistic and Proapoptogenic Cytotoxicity Drug Design and Targeted Delivery.

In a world where cancer continues to be a major health problem, the urgency continues to find new effective treatments. This work involved the synthesis of more than 10 anticancer fluoroquinolones (FQs) and pyridoquinoxaline (PQ) derivatives originating from FQs and studied their cytotoxicity, anti-adhesion, anti-invasion, and pro-apoptotic properties. Synthesis of the new compounds of the PQ series was carried out by reacting 1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with L-proline, 3 and 4-hydroxy proline derivatives (compounds 2a-2f), followed by reductive cyclization to yield compounds 3a-3f. Compounds 2a and 3a gave favorable activities on MCF-7 with respective IC₅₀ values of 5.9 and 0.9 μM, respectively, while the hydroxy derivatives almost lost activity on all tested cells. Due to the fact that the activity of PQs and precursor FQs was correlated to increased lipophilicity, the lipophilic FQs series 10a, 10b, 11a, and 11b were prepared by direct reaction of 1-cyclohexyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate with chloro or fluoro aniline, followed by ester hydrolysis 10a and 10b and reduction to yield the amine compounds 11a and 11b. All FQs 10a, 10b, 11a, and 11b showed very excellent cytotoxicity against all tested cell lines (mammary MCF-7, MDA-MB-231, and invasive prostate DU-145) with IC₅₀ values below 20 μM with impressively favorable lack of any cytotoxicity in normal ligament PDL fibroblasts (in 3.125-200 μM). Only FQs exerted comparable or superior anti-adhesion and anti-invasion activity versus the antineoplastic reference quercetin. Significant incremental increases in the pro-apoptogenesis Bax/anti-apoptosis Bcl ratio revealed a physiologically regulated cytotoxicity via DNA fragmentation harvested in cytolysates. The structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) reveal that planarity due to a fused polycyclic system and lipophilicity were essential requirements for anticancer PQs, whereas a high number of hydrogen bonds (HBs) and increased number of chelators, in addition to lipophilic balance, are the major requirements for anticancer FQs. In vitro cell viability assays revealed pronounced affinity for reductions in cell viabilities for the targeted PQ-bearing AuNPs versus PQsalone (induced) incubations and basal (non-induced) controls after 48 h incubation with HT29 cells. These results are very promising upon optimization of the system.