DNA minor-groove binders. Design, synthesis and biological evaluation of ligands structurally related to CC-1065, distamycin, and anthramycin
P. G. Baraldi, M. A. Tabrizi, D. Preti, F. Fruttarolo, B. Avitabile, A. Bovero, G. Pavani, M. del Carmen Nunez Carretero, and R. Romagnoli
University of Ferrara, Dipartimento di Scienze Farmaceutiche,
Via Fossato di
Mortara 17/19, 44100 Ferrara, Italy
Abstract: Many natural and synthetic anticancer agents
with the ability to interact with DNA have been discovered, but most
have little sequence-specificity and often exhibit severe toxicity to
normal tissues. Thus, there has been considerable interest in molecular
biology and human medicine to find small molecules that can alkylate
the DNA in a sequence-specific manner and modify the function of nucleic
acids irreversibly. Analogs 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 researchers' attention not only for its biological activity,
but also for its nonintercalative binding to the minor groove of double-stranded
B-DNA, where it forms a strong reversible complex preferentially at
the nucleotide sequences consisting of 4-5 adjacent adenine-thymine
(AT) base pairs. The pyrrole-amide skeleton of distamycin A has been
also used as DNA sequence-selective vehicles 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.
In the last few years, several hybrid compounds, in which derivatives
of naturally occurring antitumor agents, such as anthramycin or the
alkylating unit of the antibiotic CC-1065, have been tethered to distamycin
frames. 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 alkylating unit tethered to the oligopeptidic
frame.
*Pure Appl.Chem. 75,
141�419 (2003). An issue of reviews and research papers based on
lectures presented at the 23rd IUPAC International Symposium on the
Chemistry of Natural Products, Florence, Italy, 28 July � 2 August 2002.
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