Pyrroloquinoline antitubulin agents keep activity in paclitaxel- and daunorubicin-resistant cells
- A library of 1H-pyrrolo[3,2-c]quinolines was made and mapped by SAR, yielding compounds with low-nanomolar antiproliferative potency and very large selectivity over normal fibroblasts.
- The best derivatives kept activity in daunorubicin- and paclitaxel-resistant sublines and showed low efflux ratios, suggesting limited cross-resistance.
- A lead showed rapid absorption, moderate half-life and limited brain penetration, but zebrafish embryo toxicity pointed to a narrow therapeutic window.
💡 Points
Tubulin binders that dodge P-gp efflux are always of interest, and low efflux ratios plus retained activity in resistant lines is the right first filter. The zebrafish result is the honest sting in the tail: potent antimitotics often have a thin margin, so selectivity over fibroblasts in culture will not settle the safety question. I would look next at the binding site and how far the scaffold can be tuned toward a wider window.