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Construction and application of a Rh-Pt DNA metalloinsertor conjugate

Weidmann, Alyson G. and Barton, Jacqueline K. (2015) Construction and application of a Rh-Pt DNA metalloinsertor conjugate. Abstracts of Papers of the American Chemical Society, 249 . INOR-935. ISSN 0065-7727. https://resolver.caltech.edu/CaltechAUTHORS:20150408-082055756

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Abstract

The success of cisplatin as an anticancer agent has led to the development of a multitude of inorg. complexes for chemotherapy. In particular, rhodium metalloinsertor complexes, which selectively target base pair mismatches in DNA, have been shown to exhibit exceptional and selective cytotoxic activity in cancer cells that are deficient in mismatch repair (MMR). Here, we have synthesized and characterized a bifunctional metalloinsertor conjugate (RhPt), consisting of a rhodium mismatch recognition component tethered to a deriv. of the chemotherapeutic oxaliplatin. The RhPt complex exhibits dual binding to a DNA duplex contg. a mismatch, first through metalloinsertion at the mismatched site followed by the formation of covalent Pt-DNA adducts. It was found that RhPt displays enhanced cytotoxicity in MMR-deficient HCT116O cells compared to cisplatin and oxaliplatin as well as relative to the individual subunits. Cytotoxicity assays with caspase and poly-ADP ribose polymerase inhibitors revealed that RhPt induces apoptotic cell death, rather than the necrotic pathway triggered by metalloinsertors. Cellular uptake was probed using inductively coupled plasma mass spectrometry, and it was found that RhPt exhibits increased cellular uptake compared to control complexes, likely contributing to its enhanced activity. This and other Rh-Pt complexes will be discussed in the application of bifunctional complexes as chemotherapeutic agents.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.acs.org/content/acs/en/meetings/spring-2015.htmlOrganizationConference Website
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2015 American Chemical Society.
Record Number:CaltechAUTHORS:20150408-082055756
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150408-082055756
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56464
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Apr 2015 15:38
Last Modified:03 Oct 2019 08:14

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