The structure of the anticancer drug capecitabine was redesigned to prevent metabolic conversion to 5-fluorouracil, and its associated potentially fatal toxicities. The resulting cytidine analog, pencitabine (Pen), is a hybrid of two anticancer drugs currently in clinical use, capecitabine and gemcitabine. Pen was shown to be cytotoxic to KG-1 acute myelogenous leukemia cells in culture (IC50 = 0.13 μM), and orally active in vivo in the HCT-116 human colorectal carcinoma xenograft test system, superior to capecitabine. Due to its hybrid nature, Pen may mimic the known therapeutically advantageous combination of its parent drugs. Pen is postulated to interfere with DNA synthesis and function by inhibiting multiple nucleotide metabolizing enzymes, such as ribonucleotide reductase, thymidylate synthase and DNA polymerases, and by misincorporation into DNA. The misincorporation of the nucleoside analogs derived from Pen may result in a gain of function by two additional effects not caused by the parent drugs: inhibition of DNA (cytosine-5)-methyltransferase and DNA glycosylases involved in base excision repair.

Rational design of a novel, orally acting anticancer fluoropyrimidine, pencitabine, a hybrid of capecitabine and gemcitabine

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.