Current Medicinal Chemistry - Volume 8, Issue 5, 2001

DNA is a well characterized intracellular target but its large size and sequential nature make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this respect the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in diagnosis and treatment of cancers as well as in molecular biology. Recent progress in the development of cross linked lexitropsin oligopeptides and hairpins, which bind selectively to the minor groove of duplex DNA, is discussed. Bis-distamycins and related lexitropsins show inhibitory activity against HIV-1 and HIV-2 integrases at low nanomolar concentrations. Benzoyl nitrogen mustard analogs of lexitropsins are active against a variety of tumor models. Certain of the bis-benzimidazoles show altered DNA sequence preference and bind to DNA at 5'CG and TG sequences rather than at the preferred AT sites of the parent drug. A comparision of bifunctional bizelesin with monoalkylating adozelesin shows that it appears to have an increased sequence selectivity such that monoalkylating compounds react at more than one site but bizelesin reacts only at sites where there are two suitably positioned alkylation sites. Adozelesin, bizelesin and carzelesin are far more potent as cytotoxic agents than cisplatin or doxorubicin. A new class of 1,2,9,9a-tetrahydrocyclo- propa(c)benz(e)indole-4-one (CBI) analogs i.e., CBI-lexitropsin conjugates arising from the latter leads are also discussed.A number of cyclopropylpyrroloindole (CPI) and CBI-lexitropsin conjugates related to CC-1065 alkylate at the N3 position of adenine in the minor groove of DNA in a sequence specific manner, and also show cytotoxicities in the femtomolar range. The cross linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin, and melphalan. A new class of PBD-lexitropsin conjugates is also discussed. Certain functional models of the bleomycins (BLMs) show outstanding DNA cleavage activity comparable with that of and positionally distinct from natural BLM.

Lexitropsins are modular polyamide molecules that are designed to read the base sequence of DNA. Lexitropsins constructed of three types of subunits-pyrrole, imidazole and hydroxypyrrole-allow full recognition of DNA base sequences. Structural studies have revealed the atomic basis of this specificity. Theoretical studies have explored the effectiveness of lexitropsins in targeting a given sequence within a genome, and have been used to analyze and improve lexitropsin design.

More and more, nucleic acids have become prime targets in the development of new compounds, able to control gene expression. For the development of new sequence selective dsDNA binding ligands, one can learn a lot from existing models such as, lexitropsins, combilexins and actinomycin D. This analysis, together with the knowledge of the details on protein-DNA interactions, has inspired the assembly of unnatural amino acids in a combinatorial way to generate a dsDNA recognition library. The first selection round has led to the selection of new DNA binding molecules, which may lead on the long run to the discovery of new DNA binding motifs.

Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards, where attachment of the mustard unit to carrier molecules can change the normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to a few adenine N3 sites at the 3-end of poly(A(slash)T) sequences in the minor groove. Carrier molecules discussed for mustards are intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), polybenzamides and anilinoquinolinium salts. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine). Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed.

PNA (peptide nucleic acid) is a DNA mimic with a pseudopeptide (polyamide) backbone which can be used to target double stranded DNA with high sequence specificity. PNA therefore has great potential in the development of biomolecular tools for manipulation of DNA as well as for the development of DNA targeted gene therapeutic drugs. The status of this field is discussed in terms of PNA binding modes and mechanism as well as applications.

The last few years have represented an accelerated accumulation in detailed information about ligand-DNA interactions. A collected view of literature information is essential for advancing our understanding of the principles of ligand-DNA recognition, utilizing this valuable information for construction of a modeling database, and eventually the rational design of DNA-binding ligands possessing desired properties. This review is concentrated on structure-based information on ligand-oligodeoxyribonucleotide (DON) complexes published since 1995, especially focusing on the results obtained from NMR structure elucidation. The discussionsemphasize the sequence specific recognition of novel binding motifs or binding modules of ligand molecules rather than specific atomic details. A comprehensive list of DNA binding ligands are discussed in the text and are also summarized in a table. The DNA sequences that are recognized by specific ligand molecules as studied by NMR are annotated in a figure to provide a clear view of target selection. This review also briefly describes NMR methods for characterization and structure elucidation of ligand-DNA complexes.