A Family of Rhodium Complexes with Selective Toxicity towards Mismatch Repair-Deficient Cancers
- Creators
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Boyle, Kelsey M.
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Barton, Jacqueline K.
Abstract
Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium–oxygen ligand coordination, termed "Rh–O" metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh–O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]^(2+), all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh–O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and pK_a values of 8.1–9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh–O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment.
Additional Information
© 2018 American Chemical Society. Received: February 26, 2018; Published: April 5, 2018. Financial support for this work from the NIH (GM33309) and AMGEN is gratefully acknowledged. We thank the Department of Defense for supporting K.M.B. through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program. We also thank Paige Gannon for assisting in uptake and localization studies of the complexes. This project benefitted from the use of instrumentation made available by the Caltech Environmental Analysis Center and we gratefully acknowledge guidance from Dr. Nathan Dalleska. We also thank the Moore Foundation Center for the Chemistry of Cellular Signaling. The Caltech Center for Catalysis and Chemical Synthesis and Dr. Scott Virgil are gratefully acknowledged for assistance with enantiomeric separation. The authors declare no competing financial interest.Attached Files
Accepted Version - nihms968156.pdf
Supplemental Material - ja8b02271_si_001.pdf
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Additional details
- PMCID
- PMC5965675
- Eprint ID
- 85655
- Resolver ID
- CaltechAUTHORS:20180405-142009074
- NIH
- GM33309
- Amgen
- National Defense Science and Engineering Graduate (NDSEG) Fellowship
- Created
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2018-04-05Created from EPrint's datestamp field
- Updated
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2022-03-11Created from EPrint's last_modified field