Re-Exploring the Anthracycline Chemical Space for Better Anti-Cancer Compounds.
Merle A van GelderSabina Y van der ZandenMerijn B L VriendsRoos A WagensveldGijsbert A van der MarelJeroen D C CodéeHerman S OverkleeftDennis P A WanderJacques J C NeefjesPublished in: Journal of medicinal chemistry (2023)
The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure-activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients.
Keyphrases
- end stage renal disease
- gene expression
- circulating tumor
- dna damage
- structure activity relationship
- oxidative stress
- cell free
- transcription factor
- chronic kidney disease
- ejection fraction
- endothelial cells
- single molecule
- genome wide
- healthcare
- early breast cancer
- peritoneal dialysis
- primary care
- papillary thyroid
- squamous cell
- squamous cell carcinoma
- big data
- young adults
- childhood cancer
- induced pluripotent stem cells
- patient reported