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Novel fluorinated docetaxel analog for anti-hepatoma: Molecular docking and biological evaluation
Yun-Peng Hao1, Zheng-Yu Liu1, Cheng Xie1
1Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Abstract:
N-De-tert-butoxycarbonyl-N-[2-(1,1,1-trifluoro-2-methyl)propyloxycarbonyl]-2-debenzoyl-2-(m-fluorobenzoyl)-docetaxel (4FDT), a novel fluorinated docetaxel analog, was evaluated for its anti-hepatoma effect and possible druggability. In molecular docking studies, 4FDT coincided with paclitaxel in a part of the nucleus. In in vitro studies, 4FDT demonstrated higher anti-hepatoma activity approximately 1.5 times greater than that of docetaxel. More interestingly, 4FDT had been determined to have better anticancer effects, even 90 times greater in patient-derived xenografts (PDX) liver cancer cell lines than sorafenib. In the in vivo studies, 4FDT could effectively reduce the growth rate of liver cancer H22 and HepG2 cells. Furthermore, in a preliminary study on the ex vivo distribution of 4FDT, 4FDT-IR783 was primarily concentrated in the liver 1h after injection, and most of it was metabolized from the liver in 24h. Finally, the acute toxicity test revealed fewer side effects for 4FDT (approximately 16% than docetaxel). The water solubility, which was 11 times greater than that of docetaxel, confirmed the good druggability of 4FDT. All of these results demonstrated 4FDT's great potential to be a candidate drug for liver cancer treatment.
Insights
A novel fluorinated docetaxel analog, 4FDT, shows significant anti-hepatoma activity and improved druggability compared to docetaxel. This promising agent demonstrates potent anticancer effects in preclinical models with reduced toxicity, suggesting potential for liver cancer treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited effective therapeutic options.
- Docetaxel, a microtubule-targeting agent, is used in cancer therapy but faces challenges with efficacy and toxicity.
- Development of novel analogs with enhanced activity and improved pharmacokinetic profiles is crucial for advancing HCC treatment.
Purpose of the Study:
- To evaluate the anti-hepatoma efficacy and druggability of a novel fluorinated docetaxel analog, N-De-tert-butoxycarbonyl-N-[2-(1,1,1-trifluoro-2-methyl)propyloxycarbonyl]-2-debenzoyl-2-(m-fluorobenzoyl)-docetaxel (4FDT).
- To compare the anticancer activity and toxicity of 4FDT with existing therapies like docetaxel and sorafenib.
- To assess the pharmacokinetic properties and preliminary safety profile of 4FDT.
Main Methods:
- Molecular docking studies to predict the binding site of 4FDT.
- In vitro anti-hepatoma activity assays using liver cancer cell lines.
- In vivo studies using patient-derived xenografts (PDX) and animal models (H22, HepG2 cells).
- Ex vivo distribution studies using a labeled 4FDT analog (4FDT-IR783).
- Acute toxicity tests and water solubility measurements.
Main Results:
- 4FDT exhibited approximately 1.5 times higher anti-hepatoma activity than docetaxel in vitro.
- 4FDT demonstrated significantly greater anticancer effects (up to 90 times) than sorafenib in PDX liver cancer cell lines.
- In vivo studies showed that 4FDT effectively reduced the growth rate of H22 and HepG2 liver cancer cells.
- 4FDT showed preferential liver accumulation and rapid metabolism, with significantly reduced acute toxicity (approx. 16% of docetaxel).
- 4FDT possesses 11 times greater water solubility than docetaxel, indicating improved druggability.
Conclusions:
- 4FDT is a potent novel fluorinated docetaxel analog with superior anti-hepatoma activity compared to docetaxel and sorafenib.
- The compound demonstrates favorable pharmacokinetic properties, including liver-specific distribution and good water solubility, suggesting enhanced druggability.
- Reduced toxicity profile and potent preclinical efficacy position 4FDT as a promising candidate drug for liver cancer treatment.
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