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

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