It is nowadays widely accepted that some tumors have a niche of cells endowed with stemness features,
which may cause resistance to conventional anticancer therapies and relapse/recurrence of the malignancy.
These cells are usually referred to as cancer stem cells (CSCs) and, different from normal cancer cells, are
rather quiescent. Targeting CSCs is thus a highly challenging but promising strategy to counteract tumor
growth, and to develop innovative anticancer agents.
Here, we review the chemical, biological and multidisciplinary efforts that have been spent in targeting CSCsspecific
signaling pathways Notch and Hedgehog (Hh) for anticancer drug discovery. In particular, the use of
natural products as a valuable source of lead compounds or chemical biology tools is emphasized. Examples of
natural products functionalization through semi-synthetic transformations or total syntheses, aimed at improving
pharmacokinetics and/or pharmacodynamics properties of natural products in Notch or Hh inhibition, are
provided as well.