Overcoming Tumor Drug Resistance with High‐Affinity Taxanes: A SAR Study of C2‐Modified 7‐Acyl‐10‐Deacetyl Cephalomannines

A series of C2-modified 10-deacetyl-7-propionyl cephalomannine derivatives was designed, prepared, and biologically evaluated. Some C2 meta-substituted benzoate analogues showed potent activity against both drug-sensitive and drug-resistant tumor cells in which resistance is mediated through either P-gp overexpression or beta-tubulin mutation mechanisms. The taxoid 15 b and related compounds are of particular interest, as they are much more cytotoxic than paclitaxel, especially against drug-resistant tumor cells; they are able to kill both drug-resistant and drug-sensitive cells (low R/S ratio), and they have high affinity for beta-tubulin. Our research results led to an important hypothesis, that is, a taxane with very high binding affinity for beta-tubulin is able to counteract drug resistance, which may assist in future taxane-based drug-discovery efforts.