Antiproliferative Properties of 7,8-Ethylene Diamine Chelator-Lipophilic Fluoroquinolone
Derivatives Against Colorectal Cancer Cell Lines
Authors: Kasabri Violet , Khaleel Sara , Al-Hiari Yusuf , Haddadin Randa , Albashiti Rabab , Al-Zweri Muhammad , Bustanji Yasser 
Published: June 2021

Background:
Cancer is one of the most overwhelming diseases nowadays. It is considered the second cause
of death after cardiovascular diseases. Due to the diversity of its types, stages and genetic origin, there is no available
drug to treat all cancers. Serious side effects and resistance of existing drugs are other problems in the struggle against
cancer. In such quest, fluoroquinolones (FQs) promising as antiproliferative compounds due to safety, low cost and
lack of resistance.

Objectives:
Therefore, this work aims at developing lipophilic FQs and screening their antiproliferative activity against
colorectal cancer.

Methods:
Nine prepared FQs were investigated for antiproliferative activity utilizing in vitro SRB method. In comparison
to the antiproliferative agent cisplatin; the assessment of antiproliferative activities of these novel FQs in a panel of
Colorectal Cancer Cell (CRC) lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament
fibroblasts for safety examination was performed. Antibacterial activity (MIC) was conducted against Staphylococcus
aureus and Escherichia coli standard strains using the broth double dilution method. Antioxidant properties were suspected
as the mechanism of antiproliferative activity; thus, a DPPH test was performed to analyze radical scavenging
potency of FQs compared to ascorbic acid as reference agent. FQs compounds 3-5(a-c) were prepared, characterized
and their structure was confirmed using spectroscopy techniques.

Results:
All compounds manifested good to excellent antiproliferative activity on HT29, HCT116, and SW620 with
high safety index. The reduced series 4a, 4b and 4c exerted excellent micro to nano -molar antiproliferative activities
on HT29, HCT116, and SW620 which were stronger than the reference cisplatin against all cells. The reduced group of
compounds 4(a-c) revealed higher potency vs. both nitro and triazolo groups. On cell lines HT29, HCT116, and
SW620, reduced 4a with 7,8-ethylene diamine,the substitution revealed the highest antiproliferative efficacy
(IC50 value) approaching nano molar affinity with higher safety vs. cisplatin. The most active compound, 4a, exhibited
significant potency against HCT116, and SW620 with IC50 0.6 and 0.16 μM respectively. Novel FQs (4a, 4b and 4c)
also showed strong radical scavenging activity with IC50 values (μM) 0.06, 23, and 7.99, respectively. Exquisitely 4a
revealed a similar pattern of activity to doxorubicin, indicating a similar mechanism of action. Strong antiproliferative
and weak antibacterial activities of series 4 endorse that their mechanism involves eukaryotic topoisomerase II inhibition.
This work has revealed novel FQs with excellent anticancer activity against 5 colorectal cancer (HT29, HCT116,
SW620, CACO2, SW480) cell lines with a potential chelation mechanism due to 7,8-ethylene diamine chelator bridge.

Conclusions:
The new FQs have confirmed that more lipophilic compounds could be more active as hypothesized. The
p-halogenated aniline, N1-Butyl group in addition to 3-COOH, 8-NH2 are all essential requirements for strong antiproliferative
FQ of our FQ scaffold. This work emphasizes the role of C-8 amino as part of ethylene diamine group as an
essential requirement for antiproliferative FQs for the first time in the literature, entailing its role toward potential
antineoplastic FQs.