Coffee Filter Method Yields Cheaper Production of Cancer Drug Candidate

Researchers have developed a less costly, improved method to produce the cancer drug Z-endoxifen, which could increase the drug’s accessibility for clinical trials, according to a study published in Bioorganic & Medicinal Chemistry Letters.

Tamoxifen is a known breast cancer chemotherapeutic drug, but is not always effective due to its dependence on Z-endoxifen conversion. According to the study, Z-endoxifen is regarded as the most active metabolite of tamoxifen and has recently demonstrated a 26.3% clinical benefit in a phase 1 clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy.

According to the researchers, future studies would benefit from more efficient synthetic access to the drug. Clinical trials in the United States have suggested that applying Z-endoxifen directly can boost therapeutic response in patients and circumvent dependence on the patient’s gene, but the drug can only be produced in small amounts, which has made it costly.

However, the researchers have discovered an improved method for producing the drug that involves a process similar to filtering coffee granules from a cup of coffee.

In the production process, the researchers noted that the current high-press liquid chromatography (HPLC) purification method, which can be expensive on a larger scale, was not necessary. The existing method yields 2 variants: Z- and E-stereo isomers in a 70:30 ratio, of which HPLC was only necessary to remove the unwanted 30%. The researchers found that the ratio could be increased to 95:5 if enabled 1 step earlier in the process. At this point, a remaining 5% unwanted E-isomer can be removed through a paper filter.

The latest findings make it possible to produce dozens of grams or even kilos at high purity at the same time at a cost of production that is 1000 times lower, according to the study authors. This means that medical research groups would no longer be dependent on expensive producers to analyze the drug’s effects, the researchers noted, but they can now produce the drug themselves at a much lower cost.

The researchers concluded that the findings have implications to broaden accessibility of Z-endoxifen to many research groups for further study. To make the drug available to patients, the improved production method would need to be scaled up even further to industrial production, they noted.

Reference

Milroy LE, Koning B, Scheppingen DSV, et al. A multi-gram-scale stereoselective synthesis of Z-endoxifen. Bioorganic & Medicinal Chemistry Letters. 2018. https://doi.org/10.1016/j.bmcl.2018.03.008