Cobalt complexes with tripodal ligands: implications for the design of drug chaperones

Abstract

Extensive research is currently being conducted into metal complexes that can selectively deliver cytotoxins to hypoxic regions in tumours. The development of pharmacologically suitable agents requires an understanding of appropriate ligand-metal systems for chaperoning cytotoxins. In this study, cobalt complexes with tripodal tren (tris-(2-aminoethyl)amine) and tpa (tris-(2-pyridylmethyl)amine) ligands were prepared with ancillary hydroxamic acid, β-diketone and catechol ligands and several parameters, including: pK(a), reduction potential and cytotoxicity were investigated. Fluorescence studies demonstrated that only tpa complexes with β-diketones showed any reduction by ascorbate in situ and similarly, cellular cytotoxicity results demonstrated that ligation to cobalt masked the cytotoxicity of the ancillary groups in all complexes except the tpa diketone derivative [Co(naac)tpa](ClO(4))(2) (naac = 1-methyl-3-(2-naphthyl)propane-1,3-dione). Additionally, it was shown that the hydroxamic acid complexes could be isolated in both the hydroxamate and hydroximate form and the pK(a) values (5.3-8.5) reveal that the reversible protonation/deprotonation of the complexes occurs at physiologically relevant pHs. These results have clear implications for the future design of prodrugs using cobalt moieties as chaperones, providing a basis for the design of cobalt complexes that are both more readily reduced and more readily taken up by cells in hypoxic and acidic environments.

An Esculetin–Cobalt(III) Archetype for Redox‐Activated Drug Delivery Platforms with Hypoxic Selectivity

“…The peak potentials found for the anodic and cathodic scan provided the average potential of –1.00 ± 0.02 V vs. Fc/Fc + for the Co 3+ /Co 2+ processes in MeCN. This value is similar to that found for the complex [Co(cat)(tpa)]ClO 4 (H 2 cat = 2,3‐naphthalenediol), described by Hambley and co‐workers in DMF ( E 1/2 = –1.02 V vs. Fc/Fc + ) . The Co 3+ /Co 2+ potentials were converted to the standard hydrogen electrode (SHE) values by the addition of 0.40 V in accord with Gagne et al (Table ), in an attempt to verify whether the reduction potential would fall into the accepted ideal range of –0.2 to –0.4 V vs. SHE for a compound to be reduced in vivo , , .…”

Investigation of Cobalt(III)‐Tetrachlorocatechol Complexes as Models for Catechol‐Based Anticancer Prodrugs

“…The lack of reactivity is attributed to the redox potential for Co 3+ /Co 2+ (–0.91 V for 1 and –1.15 V vs. Fc/Fc + for 2 ), whose values are too negative to allow reduction by ascorbic acid and sodium dithionite. These potentials are comparable to that measured in DMF ( E 1/2 = –1.02 V vs. Fc/Fc + ) for the complex [Co(CAT)(TPA)]ClO 4 , whose reduction by ascorbic acid (10‐fold excess) was also not observed . Nonetheless, the complex [Co(esc)(py 2 en)]ClO 4 did also present a potential in MeCN in the same range (–1.0 V vs. Fc/Fc + ), and was reduced by dithionite with an [O 2 ]‐dependent dissociation of esculetin.…”

“…Thus, the redox potential for Co 3+ /Co 2+ was found to be –0.91 ± 0.02 V and –1.15 ± 0.02 V vs. Fc/Fc + for 1 and 2 , respectively. These redox potentials are in the range of those reported for the complexes [Co(CAT)(TPA)]ClO 4 (CAT = 2,3‐naphthyldiol) ( E pc = –1.02 V vs. Fc/Fc + in DMF), [Co(Br 4 Cat)(L)] + (–1.07 to –1.64 V vs. Fc/Fc + in MeCN), [Co(Me 3 TPA)(TCC)] + (–0.4 V vs. Fc/Fc + in MeCN), and [Co(esc)(py 2 en)] + (esc = esculetin) ( E 1/2 = –1.00 V vs. Fc/Fc + in MeCN) …”

“…Nonetheless, in a recent paper published by our group, successful release of esculetin (or 6,7‐dihydroxycoumarin) from the complex [Co(esc)(py 2 en)]ClO 4 upon Co 3+ /Co 2+ reduction by dithionite was observed, with an oxygen‐dependent dissociation rate . Interestingly, the redox potential of this complex in MeCN (–1.00 V vs. Fc/Fc + ) is similar to that measured in DMF for [Co(CAT)(TPA)]ClO 4 (–1.02 V vs. Fc/Fc + ) . Thus, we have decided to further investigate this class of complexes, using tetrachorocatechol as a drug model for cobalt(III)‐catechol prodrugs.…”

“…The ortho ‐diphenol moiety is present in a number of molecules with anticancer activity such as quinalizarine, a strong casein kinase (CK2) inhibitor, and cabozantinib (Cometriq R ), an inhibitor of tyrosine kinase receptors (TKI) that is FDA‐approved to treat advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and under trial for renal, prostate, hepatocellular, and lung cancers . Hambley and co‐workers have investigated the complex [Co(CAT)(TPA)]ClO 4 {CAT = 2,3‐naphthyldiol and TPA = tris(2‐pyridylmethyl)amine} . Dissociation of the CAT ligand associated with Co 3+ /Co 2+ by ascorbic acid was not observed.…”