Novel N-phenyl-2-(aniline) benzamide hydrochloride salt development for colon cancer therapy
Yan Peng1, Ying Peng1, Wei Zhang1
1School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Introduction:
N-phenyl-2-(aniline) analog N53 is a previously discovered dual inhibitor of Topo I and COX-2, which exhibited significant anti-colon cancer activity in vitro, but the poor solubility and moderate anti-cancer activity in vivo hindered its further development.
Methods:
To rectify the suboptimal drug properties of N53, a series of salt forms were developed and further evaluated through in vivo and in vitro experiments.
Results:
The hydrochloride (N53·HCl) has a well-characterized crystal structure and its solubility reached 540.1 μg/mL, which is nearly 1,700 times higher than that of N53 (0.32 μg/mL). Increasing the N53 solubility consistently promotes its effective concentration, further enhancing the COX-2/Topo I inhibitory activity and the anti-tumor activity in vitro (IC50 values of 2.95 ± 0.08 μM for HT29 cells, 7.99 ± 0.85 μM for RKO cells, 10.94 ± 1.30 μM for HCT116 cells), as well as the anti-proliferative and pro-apoptotic activity. Meanwhile, its oral pharmacokinetic property in vivo is also improved. The elimination half-life (T1/2) is prolonged from 10.78 to 22.29 h, the maximum plasma concentration (Cmax) is increased 2-fold, and the area under the plasma drug concentration-time curve (AUC0-∞) is increased 3-fold. In colon cancer xenograft mouse models, the tumor inhibition rate of N53·HCl was 53.7%, superior to that of N53 (34.7%). Moreover, the results of HE staining showed that N53·HCl had no obvious toxic effects and side effects on other organs, indicating that it was safe in vivo.
Discussion:
This study demonstrated that N53·HCl exhibits superior pharmacokinetic properties, anti-colon cancer efficacy, and safety, providing a promising drug candidate for colon cancer therapy.
Insights
The novel hydrochloride salt form, N53·HCl, significantly enhances the anti-colon cancer efficacy of N53 by improving its solubility and pharmacokinetic properties. This improved drug candidate demonstrates superior in vivo anti-tumor activity and safety for colon cancer therapy.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- N53, a dual Topo I and COX-2 inhibitor, showed in vitro anti-colon cancer activity but was limited by poor solubility and moderate in vivo efficacy.
- Developing N53 into a viable colon cancer therapeutic required addressing its suboptimal drug properties.
Purpose of the Study:
- To improve the drug properties of N53 by developing and evaluating its salt forms.
- To assess the enhanced anti-colon cancer efficacy, pharmacokinetic profile, and safety of N53·HCl in vitro and in vivo.
Main Methods:
- Synthesis and characterization of N53 salt forms, focusing on N53·HCl.
- In vitro assays to evaluate cytotoxicity, anti-proliferative, and pro-apoptotic activities.
- In vivo studies in colon cancer xenograft mouse models to assess anti-tumor efficacy and pharmacokinetics.
- Histopathological examination (HE staining) to evaluate in vivo safety and toxicity.
Main Results:
- N53·HCl exhibited a 1,700-fold increase in solubility compared to N53 (540.1 μg/mL vs. 0.32 μg/mL).
- N53·HCl demonstrated enhanced in vitro anti-tumor activity with lower IC50 values and improved anti-proliferative and pro-apoptotic effects.
- In vivo, N53·HCl showed a prolonged elimination half-life (22.29 h vs. 10.78 h), increased Cmax (2-fold), and AUC0-∞ (3-fold), with a tumor inhibition rate of 53.7% compared to 34.7% for N53.
- HE staining indicated no significant toxic effects of N53·HCl on major organs.
Conclusions:
- N53·HCl possesses significantly improved solubility, pharmacokinetic properties, and in vivo anti-colon cancer efficacy compared to the parent compound N53.
- N53·HCl demonstrates a favorable safety profile, making it a promising drug candidate for colon cancer treatment.
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