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

Abstract

Geldanamycin ( GDM ) has been modified by different type neutral/acidic/basic substituents ( 1 – 7 ) and by quinuclidine motif ( 8 ), transformed into ammonium salts ( 9 – 13 ) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC 50 s = 0.09–1.06 µM). Transformation of 8 into salts 9 – 13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC 50 ∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC 50 ∼2 µM to IC 50 ∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13 . Docking studies showed that complexes between quinuclidine-bearing 8 – 13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.

Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs

“…Hence, the benzyl-triazole hybrids 5a – c and 6a – c , with less bulky ends of the arm, are the most active ones (IC 50 s = 2.04 − 3.97 nM) among this group derivatives. In contrast to these derivatives, combining of colchiceine with geldanamycin into one scaffold via triazole linkage, resulted in a decreased anticancer activity, when referred to 1 , and enhanced potency, when referred to geldanamycin itself 52 . In turn, the result of the anticancer studies of 7 - and 8 -type derivatives is quite surprising ( Table 2 ), taking into account the length and bulkiness of substituents introduced by the Heck reaction ( Figure 4 ).…”

Structural diversity and biological relevance of benzenoid and atypical ansamycins and their congeners

“…36) and were found to be better inhibitors of Hsp90 (K D s 0.8-0.9 mM) than geldanamycin, reblastatin or 92. 46,49 Postulated binding modes of these derivatives revealed key stabilizing interactions with K43 of Hsp90 (K58, in human ortholog). A very good affinity of 102-104 to the target in cells was in line with high activities against several cancer cell lines, even comparable or better when referred to standard compounds (Table 2).…”

“…34), and decreased toxicity in normal cells at conserved anticancer effects. 49 The use of 105 as mixtures with potentiators as polyethylenimine and doxorubicin enhanced anticancer activities at the expense of increased toxicity. Studies of these benzoquinone-C 15 derivatives demonstrated lipophilicity on the level c log P ¼ 2-3, which rather favors high potency, with a relatively increased toxic effects.…”

“…46 Energy barrier of the interconversion between the two opposite atropisomeric forms of benzenoid-C 15 ansamycins was reported as in the range from $16 to 37 kcal mol À1 . [48][49][50] The presence of an N-methylated lactam within the ansa chain of ansamitocins and maytansine implies, already in the 'free' form in solution or in solid, the formation of cis-lactam atropisomer, ready to be bound with the target (Fig. 1 and 4).…”

Cascade Transformation of the Ansamycin Benzoquinone Core into Benzoxazole Influencing Anticancer Activity and Selectivity

“…13 Therefore, many different approaches involving semisynthetic, mutasynthetic, and genetic manipulations have been applied to benzenoid ansamycins in order to reduce the quinone, improve useful biological potency, and decrease toxicity. 9,14−22 Modifications of the GDM core via the fusion of additional rings, imidazole, morpholine, benzo[g]quinoxaline, benzoxazine, oxazolidine, and tetrahydrodiazepine at C(17)−C (18), were rarely accompanied by reduction of the quinone core. Moreover, reported synthetic strategies did not enable further tailoring of the structure of the attached substituent to the core toward interactions with the target (heat shock protein Hsp90).…”