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
Anti-Cancer Agents in Medicinal Chemistry
Title: Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores
Volume: 7 Issue: 1
Author(s): Rajsekhar Guddneppanavar and Ulrich Bierbach
Affiliation:
Keywords: Platinum drugs, intercalators, minor-groove binders, cancer chemotherapy, adenine, transcription factor, acridine
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.
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Guddneppanavar Rajsekhar and Bierbach Ulrich, Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores, Anti-Cancer Agents in Medicinal Chemistry 2007; 7 (1) . https://dx.doi.org/10.2174/187152007779313991
DOI https://dx.doi.org/10.2174/187152007779313991 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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