minor groove binders

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Hybrid Molecules Based on Distamycin a as Potential Antitumor Agents

Journal Title, Volume, Page: 
Volume 2006, Issue 7, Plenary and Invited Lectures ICHC-20, pp. 20-34
Year of Publication: 
2006
Authors: 
Abdel Naser Zaid
An-Najah National University, College of Pharmacy, Nablus, Palestine
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
Pier Giovanni Baraldi
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Delia Preti
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Francesca Fruttarolo
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Mojgan Aghazadeh Tabrizi
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Antonietta Iaconinoto
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Maria Giovanna Pavani
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Maria Dora Carrion
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Carlota Lopez Cara
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Romeo Romagnoli
University of Ferrara, Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
Preferred Abstract (Original): 

Many natural and synthetic anticancer agents with the ability to interact with DNA have been discovered, but most of them have relatively low therapeutic index. This is probably related to the fact that these derivatives cause DNA damage in an unspecific manner, inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. For these reasons, there has been considerable interest in finding small molecules able to alkylate the DNA with a much higher degree of sequence specificity and to modify the function of nucleic acids irreversibly. Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A  has driven researcher's attention not only for the  biological activity, but also for its non intercalative binding to the minor groove of doublestranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has also been used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of  distamycin itself. The DNA alkylating and cytotoxic activities against several tumor cell lines  are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame.   

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Ranking Ligand Affinity For The DNA Minor Groove By Experiment And Simulation

Journal Title, Volume, Page: 
American Chemical Society Med. Chem. Lett., 2010, 1 (8), pp 376–380 DOI: 10.1021/ml100047n
Year of Publication: 
2010
Authors: 
Hasan Y. Alniss
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
Simon P. MacKay
University of strathclyde, Glasgow, UK
John A. Parkinson
University of strathclyde, Glasgow, UK
Preferred Abstract (Original): 

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor groove binders (MGBs) with DNA is not fully understood. In 2003, we reported the first example of a thiazole-containing MGB that bound in a phase-shifted pattern that spanned six base pairs rather than the usual four (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, NMR spectroscopy, isothermal titration calorimetry, and molecular dynamics, we have established that the flanking bases around the central four being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences.

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