Targeting critical regions in genomic DNA with AT-specific anticancer drugs

Abstract

Cellular DNA is not a uniform target for DNA-reactive drugs. At the nucleotide level, drugs recognize and bind short motifs of a few base pairs. The location of drug adducts at the genomic level depends on how these short motifs are distributed in larger domains. This aspect, referred to as region specificity, may be critical for the biological outcome of drug action. Recent studies demonstrated that certain minor groove binding (MGB) drugs, such as bizelesin, produce region-specific lesions in cellular DNA. Bizelesin binds mainly T(A/T)(4)A sites, which are on average scarce, but occasionally cluster in distinct minisatellite regions (200-1000 bp of approximately 85-100% AT), herein referred to as AT islands. Bizelesin-targeted AT islands are likely to function as strong matrix attachment regions (MARs), domains that organize DNA loops on the nuclear matrix. Distortion of MAR-like AT islands may be a basis for the observed inhibition of new replicon initiation and the extreme lethality of bizelesin adducts (<10 adducts/cell for cell growth inhibition). Hence, long AT-islands represent a novel class of critical targets for anticancer drugs. The AT island paradigm illustrates the potential of the concept of regional targeting as an essential component of the rational design of new sequence-specific DNA-reactive drugs.

Interactions of DNA with H2TMPyP4+and Ru(II)TMPyP4+: Probable Lead Compounds for African Sleeping Sickness

“…Porphyrins and metalloporphyrins are found widely in nature and are used by organisms as cofactors for a variety of enzymes and specialized proteins (Li et al, 1996). Biological effects of porphyrin-derivatives depend strongly on their physico-chemical properties (Woynarowski, 2002). The porphyrin core is planar but shielded by peripheral substituents (Lee et al, 2001).…”

“…Cationic porphyrins act as inhibitor of human telomerases, a receptor for peptides and a specific probe of DNA structures (Tjahjono et al, 2001;Woynarowski, 2002). They have been found to associate with DNA in various modes (Fiel, 1989;Lee et al, 2002;Pasternack and Gibbs, 1989).…”

DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

“…The sequence selectivity observed with short fragments of DNA was preserved in the intracellular environment of yeast as revealed by the occurrence of adduct formation in AT-rich sequences along the MFA2 gene of S. cerevisiae. In addition to AT sequence specificity, the distribution of adducts in domains of the genome, referred to as region specificity, may also contribute to the biological outcome (53).…”

Interaction of an Fe derivative of TMAP (Fe(TMAP)OAc) with DNA in comparison with free-base TMAP

“…Porphyrins and metalloporphyrins are found widely in nature and are used by organisms as cofactors for a variety of enzymes and other specialized proteins [2]. Biological effects of porphyrin derivatives depend strongly on their physico-chemical properties [3]. The porphyrins core is plannar but shielded by peripheral substituents [4].…”

“…Cationic porphyrins act as an inhibitor of human telomerases, a receptor for peptides, and a specific probe of DNA structures [3,[17][18][19].…”