Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 17, 14 Issues, 2017


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Institut de Chimie de Clermont-Ferrand
ICCF-CNRS UMR 6296
Université Clermont Auvergne
Clermont-Ferrand
France


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Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores



Anti-Cancer Agents in Medicinal Chemistry, 7(1): 125-138.

Author(s): Rajsekhar Guddneppanavar and Ulrich Bierbach.

Affiliation: Department of Chemistry,Wake Forest University, Winston-Salem, NC 27109-7486, USA.

Abstract

The minor-groove is an important receptor for enzymes and proteins involved in the processing and expression of genomic DNA. Small molecules capable of interfering with these processes by virtue of their ability to form adducts within the recognition sequences targeted by these enzymes/proteins have potential applications as cytotoxic and generegulating agents. Until recently, the targeting of the minor groove by platinum-based agents has been a widely unexplored opportunity. As part of this focused review on irreversible minor-groove modifying agents acting on adenine-N3, we summarize work performed in our laboratory and by our collaborators on a novel platinum-acridine conjugate, PTACRAMTU ([PtCl(en)(ACRAMTU)](NO3)2, en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3- dimethylthiourea, acridinium cation). The design of this agent as a non-cisplatin type pharmacophore has led to a groundbreaking discovery, the unprecedented intercalator-driven formation of platinum-adenine-N3 adducts in the minor groove of DNA. The minor-groove reactivity of PT-ACRAMTU represents a new paradigm in platinum-DNA interactions, which opens new avenues in the design of platinum-based therapeutics acting by a mechanism different from that of agents currently in clinical use.

Keywords:

Platinum drugs, intercalators, minor-groove binders, cancer chemotherapy, adenine, transcription factor, acridine.



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Article Details

Volume: 7
Issue Number: 1
First Page: 125
Last Page: 138
Page Count: 14
DOI: 10.2174/187152007779313991
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