Abstract
Recent decades have witnessed the emergence of Au(i) bis-N-heterocyclic carbenes (NHCs) as potential anticancer agents. However, these systems exhibit little interaction with serum proteins (e.g., human serum albumin), which presumably impacts their pharmacokinetic profile and tumor exposure. Anticancer drugs bound to human serum albumin (HSA) often benefit from significant advantages, including longer circulatory half-lives, tumor targeted delivery, and easier administration relative to the drug alone. In this work, we present Au(i) bis-NHCs complexes, 7 and 9, capable of binding to HSA. Complex 7 contains a reactive maleimide moiety for covalent protein conjugation, whereas its congener 9 contains a naphthalimide fluorophore for non-covalent binding. A similar drug motif was used in both cases. Complexes 7 and 9 were prepared from a carboxylic acid functionalized Au(i) bis-NHC (complex 2) using a newly developed post-synthetic amide functionalization protocol that allows coupling to both aliphatic and aromatic amines. Analytical, and in vitro techniques were used to confirm protein binding, as well as cellular uptake and antiproliferative activity in A549 human lung cancer cells. The present findings highlight a hitherto unexplored approach to modifying Au(i) bis-NHC drug candidates for protein ligation and serve to showcase the relative benefits of covalent and non-covalent HSA binding.
Highlights
Bis-N-heterocyclic carbene gold(I) complexes have attracted interest as potential metal-based anticancer chemotherapeutics.[1,2,3] Inhibition of the mitochondria-localized enzyme thioredoxin reductase 2 (TrxR 2) has been demonstrated as the main mode of action for this class of compounds.[2,4] in many instances, the phenotypic response is less than ideal
N-heterocyclic carbenes (NHCs)-Au-OH (Fig. 1B) was combined with an imidazolium tert-butyl ester and allowed to react at 90 C overnight in toluene. This was followed by a water wash to give an estermodi ed Au(I) Bis-N-heterocyclic carbene (bis-NHC) (Au-ester, see Fig. 2B) in 75% yield
In accord with the literature,[33,34] we found that attachment of a naphthalimide moiety to an Au(I) bis-NHC motif facilitated binding to bovine serum albumin (BSA).[8]
Summary
Bis-N-heterocyclic carbene (bis-NHC) gold(I) complexes have attracted interest as potential metal-based anticancer chemotherapeutics.[1,2,3] Inhibition of the mitochondria-localized enzyme thioredoxin reductase 2 (TrxR 2) has been demonstrated as the main mode of action for this class of compounds.[2,4] in many instances, the phenotypic response is less than ideal. Human serum albumin (HSA) is the most abundant protein in blood serum.[11] It has been widely investigated as a carrier for drug molecules.[12,13] Albumin binding with anticancer agents can be accomplished using either covalent or non-covalent means.[14] The resulting adducts typically bene t from improved pharmacokinetics, facilitated formulation, and tumour targeted drug delivery in vivo.[15,16] The bene t of SA binding is underscored by the clinical effectiveness of aldoxorubicin (INNO206; human serum albumin (HSA)-coupled doxorubicin derivative) and Abraxane® (HSA based nanoparticle encapsulation of paclitaxel) for the treatment of sarcoma,[17] breast cancer,[18] lung cancer,[19] and pancreatic cancer.[20] Several other HSA-anticancer drug conjugates are currently in clinical trials. We sought to develop a synthetic method that would allow access to both covalently and non-covalently bound Au(I) bis-NHC serum albumin adducts, and do so without affecting the metal centre active site (see Fig. 1B)
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