Anticancer activity and toxicity of new quaternary ammonium geldanamycin derivative salts and their mixtures with potentiators

Geldanamycin (GDM) has been modified by different type neutral/acidic/basic substituents (1–7) and quinuclidine motif (8), transformed into ammonium salts (9–13) at C(17). These compounds have characterised spectroscopic x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 HeLa (IC50s = 0.09–1.06 µM). Transformation of 9–13 reduces toxicity (by 11-fold) attractive potency, e.g. MCF-7 cell line (IC50?2 Our studies show that higher water solubility contributes to lower healthy CCD39Lu HDF cells. The use 13 mixtures with potentiators PEI DOX enhanced anticancer effects from IC50?2 µM IC50?0.5 SKBR-3, SKOV-3, PC-3 cancer cells, relative 13. Docking showed complexes between quinuclidine-bearing 8–13 Hsp90 are stabilised extra hydrophobic interactions the C(17)-arms K58 or Y61 Hsp90.