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An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency

Komor, Alexis C. and Barton, Jacqueline K. (2014) An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency. Journal of the American Chemical Society, 136 (40). pp. 14160-14172. ISSN 0002-7863. PMCID PMC4195389. doi:10.1021/ja5072064. https://resolver.caltech.edu/CaltechAUTHORS:20140929-091130056

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Abstract

Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity and exhibit unique cell-selective cytotoxicity, targeting mismatch repair (MMR)-deficient cells over MMR-proficient cells. Here we describe a new generation of metalloinsertors with enhanced biological potency and selectivity, in which the complexes show Rh–O coordination. In particular, it has been found that both Δ- and Λ-[Rh(chrysi)(phen)(DPE)]2+ (where chrysi =5,6 chrysenequinone diimmine, phen =1,10-phenanthroline, and DPE = 1,1-di(pyridine-2-yl)ethan-1-ol) bind to DNA containing a single CC mismatch with similar affinities and without racemization. This is in direct contrast with previous metalloinsertors and suggests a possible different binding disposition for these complexes in the mismatch site. We ascribe this difference to the higher pK_a of the coordinated immine of the chrysi ligand in these complexes, so that the complexes must insert into the DNA helix with the inserting ligand in a buckled orientation; spectroscopic studies in the presence and absence of DNA along with the crystal structure of the complex without DNA support this assignment. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than cisplatin and N-methyl-N′-nitro-nitrosoguanidine (MNNG, a common DNA-alkylating chemotherapeutic agent). Moreover, the activities of the new metalloinsertors are coupled with high levels of selective cytotoxicity for MMR-deficient versus proficient colorectal cancer cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja5072064DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ja5072064PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/ja5072064PublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195389/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice. Received: July 16, 2014. Publication Date (Web): September 25, 2014. Financial support for this work from the NIH (GM33309) is gratefully acknowledged. We also thank the National Science Foundation for a Graduate Research Fellowship to A.C.K. This project benefitted from the use of instrumentation made available by the Caltech Environmental Analysis Center. Lawrence Henling and Dr. Michael K. Takase (Caltech) are gratefully acknowledged for X-ray crystallographic structural determination. The Bruker KAPPA APEXII X-ray diffractometer was purchased via an NSF CRIF:MU award to the California Institute of Technology (CHE-0639094). The Caltech catalysis center is gratefully acknowledged for assistance with enantiomeric separation. We thank R. Diamond for expertise in flow cytometry. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHGM33309
NSF Graduate Research FellowshipUNSPECIFIED
NSFCHE-0639094
Issue or Number:40
PubMed Central ID:PMC4195389
DOI:10.1021/ja5072064
Record Number:CaltechAUTHORS:20140929-091130056
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140929-091130056
Official Citation:An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency Alexis C. Komor and Jacqueline K. Barton Journal of the American Chemical Society 2014 136 (40), 14160-14172
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50082
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:29 Sep 2014 23:06
Last Modified:10 Nov 2021 18:51

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