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Pancreatic cancer is a malignancy with a high mortality rate, accounting for 37 000 people annually in Japan. It is rarely diagnosed in a resectable state, and effective medicines for its advanced stage are scarce. Some pancreatic cancer is hereditary, and ~10% have germline mutations of Breast cancer 1/2 (BRCA1/2). BRCA1/2 are key molecules involved in homologous recombination to repair DNA double-strand break. Platinum-based drugs and poly Adenosine diphosphate ribose (ADP) ribose polymerase inhibitors that induce synthetic lethality would be theoretically effective in patients with loss-of-function mutations in BRCA1/2. Strictly speaking, some discrepancy between the pathogenicity of BRCA1/2 and their drug sensitivity might be expected. Hence, we report that platinum-based anticancer agents and poly ADP ribose polymerase inhibitors were effective against pancreatic cancer bearing BRCA2 p.I3169M fs*48., (© The Author(s) 2023. Published by Oxford University Press.)

Although curcumin and its analogs exhibit anticancer activity, they are still not used as anticancer drugs because of their water insolubility and extremely poor bioavailability. This study describes the development of water-soluble prodrugs of GO-Y030, a potent antitumor C5-curcuminoid, in an attempt to enhance its bioavailability. These prodrugs release the parent compound via a retro-thia-Michael reaction. To endow sufficient hydrophilicity onto GO-Y030 via a single thia-Michael reaction of an aqueous entity, we used a modified glycoconjugate with a thiol group. The water-solubilizing motif was installed on GO-Y030 by the thia-Michael reaction of propargyl-polyethylene glycol (PEG)-thiol and subsequent click chemistry (CuAAC) reaction with 1-glycosyl azide. Turbidity measurements revealed a significantly improved water solubility of the prodrugs, demonstrating that disaccharide conjugates were completely dissolved in water at 100 µM. Their cytotoxicity was comparable to that of the parent compound GO-Y030, indicating the gradual in situ release of GO-Y030. The release of GO-Y030 from GO-Y199 via the retro-thia-Michael reaction was demonstrated through a degradation study in water. Our retro-thia-Michael reaction-based prodrug system can be used for targeting cancer cells.