Taxane anticancer agents, their pharmaceutical compositions and their use

Background

Despite advances in chemotherapeutic interventions, cancer remains the second largest cause of death in the United States. Paclitaxel and docetaxel are two extensively used chemotherapeutic drugs for various forms of cancer, including ovarian, lung, and breast cancers. However, their lack of tumor specificity leads to high levels of system toxicity and severe side effects. Additionally, the onset of multi-drug resistance illustrates the necessity for the development of new-generation taxoids with superior pharmacological properties and potency against various types of cancer.

Technology

The inventors have developed new taxane anticancer compounds designed with carbamate substituents at the C-10 position, which minimizes interactions with P-glycoprotein to enhance tumor specificity and reduce system toxicity. The compounds exhibit 1-3 orders of magnitude lower cytotoxicity to human normal cells compared to typical human cancer cells, while being 1-2 orders of magnitude more potent than paclitaxel and docetaxel against multiple drug-sensitive and drug-resistant cancer cell lines. Additionally, the incorporation of 3-OCF3 or 3-OCHF2 groups at the C-2 benzoate position help combat multidrug resistance, and improve the compounds’ metabolic stability and binding affinity to target molecules.