Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

Abstract

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumors. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902(butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

Probing cytochrome P450 bioactivation and fluorescent properties with morpholinyl-tethered anthraquinones

“…10,11 The latter is likely to follow DNA intercalation via the planar anthraquinone pharmacophore, which we have explored to discover libraries of dual-targeting DNA-affinic covalent binding agents. [12][13][14][15][16][17][18] The anthraquinone also plays a key part in the anticancer drug mitoxantrone (3) and DRAQ5 (4), a far-red DNA label used to detect nuclei and quantify DNA content in live or fixed cells. 19,20 The anthraquinone possesses fluorescent properties that can be exploited in measuring nuclear or cytoplasmic events.…”

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

“…Therefore, there is a clinical need for second-generation TOP2 inhibitors that can circumvent these mechanisms of drug resistance. Accordingly, a series of modified, anthraquinone-based compounds have been developed that combine the capability of class I TOP2 inhibitors to induce DSBs with the DNA damaging ability of alkylating agents [9][10][11] . The rationale for development of these multi-functional DNA damaging agents is that they should induce genetic damage to such an extent that it cannot be tolerated even in the presence of mutations that compromise specific DNA repair, checkpoint or apoptotic pathways.…”