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An unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency.

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... Full description

Journal Title: Journal of the American Chemical Society October 8, 2014, Vol.136(40), pp.14160-14172
Main Author: Komor, Alexis C
Other Authors: Barton, Jacqueline K
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
ID: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja5072064
Link: http://search.proquest.com/docview/1639495529/?pq-origsite=primo
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recordid: proquest1639495529
title: An unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency.
format: Article
creator:
  • Komor, Alexis C
  • Barton, Jacqueline K
subjects:
  • Antineoplastic Agents–Chemistry
  • Base Pair Mismatch–Metabolism
  • Base Sequence–Pharmacology
  • Cell Death–Drug Effects
  • Cell Proliferation–Drug Effects
  • DNA–Chemistry
  • Hct116 Cells–Genetics
  • Humans–Metabolism
  • Ligands–Chemistry
  • Models, Molecular–Genetics
  • Nucleic Acid Conformation–Metabolism
  • Oligonucleotides–Chemistry
  • Organometallic Compounds–Metabolism
  • Rhodium–Pharmacology
  • Structure-Activity Relationship–Chemistry
  • Antineoplastic Agents
  • Ligands
  • Oligonucleotides
  • Organometallic Compounds
  • DNA
  • Rhodium
ispartof: Journal of the American Chemical Society, October 8, 2014, Vol.136(40), pp.14160-14172
description: 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 Delta - and Lambda -[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 pKa 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.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja5072064
fulltext: no_fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleAn unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency.
creatorKomor, Alexis C ; Barton, Jacqueline K
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subjectAntineoplastic Agents–Chemistry ; Base Pair Mismatch–Metabolism ; Base Sequence–Pharmacology ; Cell Death–Drug Effects ; Cell Proliferation–Drug Effects ; DNA–Chemistry ; Hct116 Cells–Genetics ; Humans–Metabolism ; Ligands–Chemistry ; Models, Molecular–Genetics ; Nucleic Acid Conformation–Metabolism ; Oligonucleotides–Chemistry ; Organometallic Compounds–Metabolism ; Rhodium–Pharmacology ; Structure-Activity Relationship–Chemistry ; Antineoplastic Agents ; Ligands ; Oligonucleotides ; Organometallic Compounds ; DNA ; Rhodium
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descriptionRhodium 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 Delta - and Lambda -[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 pKa 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.
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