Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy
Graphical abstract
Introduction
Colon cancer is one of the common malignancies with the third-highest morbidity and second-highest mortality worldwide in 2020 [1,2]. Chemotherapy plays an important role throughout the treatment of colon cancer especially for advanced colon cancer [3]. The clinical first-line chemotherapeutic drugs for advanced colon cancer are mainly 5-FU and oxaliplatin, both of which are limited by their non-selective cytotoxicity and serious side effects [4].
Given the progression characterized by alteration in multiple molecular pathways, developing novel chemotherapeutic drugs against colon cancer became challenging. Targeting multiple highly expressed proteins can provide ideas for the development of such drugs.
Topoisomerase I (Topo I) is overexpressed in around 50% of primary colon cancer compared with normal tissues, closely associated with the rapid proliferation of tumor cells [5,6]. Irinotecan is a Topo I inhibitor possessing greater water solubility than precursor camptothecin with superior anticancer efficiency and comparatively low toxicity in vivo [[7], [8], [9]]. Cyclooxygenase-2 (COX-2) is another highly expressed protein in colon cancer for there are about 40%–50% of colon adenomas and 80%–90% of colon cancer tissues exhibit overexpression of COX-2 [10,11]. Overexpressed COX-2 contributes to cancer progression by inhibiting apoptosis and promoting angiogenesis and invasion [[12], [13], [14], [15]]. It was verified that the chemotherapy regimen combining irinotecan and celecoxib could enhance anticancer activity and decrease toxicity, while this combined therapy involved drug-drug interaction which prevented their clinical application [[16], [17], [18], [19]]. Development of pharmaceutical molecules with dual inhibition of Topo I and COX-2 could not only circumvent the potential risks of combined administration but also provide an alternative for colon cancer therapy drug discovery.
In the current study, we focused on the development of pharmaceutical molecules with both Topo I and COX-2 inhibitory activities. A series of N-phenyl-2-(phenylamino)benzamide derivatives with potential dual inhibitory effects of Topo I and COX-2 based on pseudocycle strategy and combination principle were developed in the previous study [20]. But, all of them suffered from poor efficiency (IC50 > 30 μM for Topo I and COX-2) and undesirable water solubility. Encouraged by several successful works that improve target inhibition and water solubility by introducing polar groups such as sulfamide and ethylene glycol derivatives, we decided to apply this strategy to improve target inhibition and aqueous solubility of dual inhibitors [[21], [22], [23], [24], [25]]. We selected I-1 (IC50 = 33.64 ± 3.99 μM for Topo I, IC50 = 33.61 ± 1.15 μM for COX-2 and water solubility <1 μg/mL) with relatively high activity as the scaffold for modification. Since the 4-OMe of I-1 has not been explored adequately even though it had great potency for structure modification, we choose 4-OMe as the modified site. We designed and synthesized a series of novel tolfenamic acid derivatives modified with polar groups such as sulfamide and ethylene glycol derivatives to obtain highly potent Topo I and COX-2 dual inhibitors for colon cancer therapy.
Section snippets
Chemistry
In order to improve the pharmacological activity, we proceeded a systematic modification to I-1. The synthetic protocols were established in Scheme 1, Scheme 2, Scheme 3, Scheme 4. Generally, amines 4, 7, 11 and 13 were prepared through nucleophilic substitution or condensation reaction and catalytic hydrogenation. Sulfanilamide and 4-aminobenzamide were commercially purchased. Tolfenamic acid reacted in a condensation reaction with amines to obtain W1 – W6, W9, W11 – W19, intermediates I1 and
Conclusion
Topo I and COX-2 are highly expressed in various types of colon cancer and are closely related to tumor progression. Development of drugs targeting both Topo I and COX-2 would hold great promise in colon cancer treatment. In our report, a collection of novel tolfenamic acid derivatives were designed and synthesized to improve the efficiency of dual-targeted inhibition as well as aqueous solubility. The results of target inhibition assay showed that most compounds had better activity compared to
Chemistry
General information. All reagents are analytical grade or chemical grade. Bruker spectrometer (Bruker Company, Germany) was used to record nuclear magnetic resonance (proton NMR 400 MHz and carbon NMR 101 MHz). Using DMSO‑d6, CDCl3 or Methanol-d4 as deuterated solvents and with tetramethylsilane (TMS) as the internal reference. Coupling constants Hz and distance unit ppm are selected as parameters to represent the values of the chemical shifts. Mass spectrometry and high-resolution mass
Author contributions
§Hu XL and Li JF contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Notes
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Thanks to the instrument platform of the School of Chemistry and Chemical Engineering, School of Pharmacy and School of Basic Medical Sciences of Lanzhou University. This research was supported by the Recruitment Program of Global Experts (1000 Talents Program); Gansu Province Science Foundation for Distinguished Young Scholars (20JR5RA304).
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Hu XL and Li JF contributed equally to this work.