Abstract
Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range.
Highlights
The discovery of cisplatin paved the way for the introduction of several platinum-based anticancer agents into clinical practice in the 1970s and 80s.1 Despite great efforts both cisplatin and the subsequently developed platinum drugs exhibit great efficiency with several downfalls, mainly resistance development and severe side effects due to general toxicity and nonspecific mode of action.[2]
We examined the inhibition of aldo–keto reductase subfamily 1C (AKR1C) enzymes known to be implicated in the pathophysiology of a variety of cancers, including breast cancer, and their potential cytotoxic effects on the model cell line of hormone-dependent breast cancer, MCF-7
We have successfully synthesized and characterized two organometallic and two trithiacyclononane-bearing ruthenium coordination compounds of pyrithione (LB) and its oxygen analog 2-hydroxypyridine N-oxide (LA). We have determined their structure in the solid state by means of single crystal X-ray diffraction and evaluated the potential of both ligands and the four ruthenium complexes as prospective anticancer agents
Summary
The discovery of cisplatin paved the way for the introduction of several platinum-based anticancer agents into clinical practice in the 1970s and 80s.1 Despite great efforts both cisplatin and the subsequently developed platinum drugs exhibit great efficiency with several downfalls, mainly resistance development and severe side effects due to general toxicity and nonspecific mode of action.[2]. The discovery of cisplatin paved the way for the introduction of several platinum-based anticancer agents into clinical practice in the 1970s and 80s.1. Despite great efforts both cisplatin and the subsequently developed platinum drugs exhibit great efficiency with several downfalls, mainly resistance development and severe side effects due to general toxicity and nonspecific mode of action.[2] The development of novel alternatives or complementary anticancer agents is urgently needed to reduce the social and economic impact of the growing occurrence of cancer. AKR1C isozymes are related to the resistance to a variety of anticancer drugs including the platinum-based drugs cisplatin, carboplatin and oxaliplatin.[7,8,9] Increased expression of AKR1Cs in these resistant cancers calls for drugs that can overcome this phenomenon by either not affecting the AKR1C levels or by inhibiting the AKR1C enzymes
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