Selective DNA interaction of the novel distamycin derivative FCE 24517 (original) (raw)
Related papers
In vitro cytotoxicity of GC sequence directed alkylating agents related to distamycin
Journal of Medicinal Chemistry, 1993
Imidazole containing analogues 7, 10, and 17 of distamycin wherein the C-terminus contain a dimethylamino moiety have been shown to selectively bind to the minor groove of GC-rich sequences. Accordingly, these agents were employed as vectors for the delivery of a variety of alkylating agents to GC-rich sequences. The dkylating agents are attached to the N-terminus of these vectors thus providing the benzoyl N-mustards (8,15, and 18 that contain one, two, and three imidazole units, respectively) and substituted acetamides 11-14. Results from the ethidium displacement m y for the formamides 7,10, and 17 and mustards 15 and 18 showed that these agents bind to calf thymus DNA, poly(dA.dT), poly(dG.dC), and also to coliphage T4 DNA, thus confirming their binding in the minor groove. The reduced binding constants of these compounds for poly(dA.dT) while still binding aa strongly, or more strongly, to poly(dG.dC) than distamycin provided evidence for their acceptance of GC sequences. Selectivity for GC-rich sequences was also indicated by CD titration studies. Titration of 10,15,17, and 18 to poly(dA.dT) produced weak drug-induced CD bands at -330 nm; however, interaction of these agents to poly(dG.dC) in equimolar drug concentrations gave strong bands in this region. Results from dialysis and cross-link gel experiments provided evidence of alkylation and cross-linking of DNA by the mustards which could explain their enhanced cytotoxicity over the formamido analogues. The bifunctional N-mustard-containing analogues 15 and 18 are significantly more cytotoxic than the monoalkylating acetamides 11-14.
Hybrid molecules based on distamycin A as potential antitumor agents
Arkivoc, 2005
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.
Nucleic Acids Research, 1991
The antiviral distamycin A and its phenyl mustard derivative FCE24517 possessing antitumor activity were tested for their ability to inhibit macromolecular synthesis in three human and one murine cell line. While distamycin A was poorly active in these systems, FCE24517 inhibited DNA synthesis efficiently, RNA synthesis to a lower extent and had little effect on protein synthesis. These findings suggest that the in vivo activity of FCE24517 derives from the specific inhibition of DNA synthesis. When the two drugs were tested on several enzymes involved in human DNA metabolism a strikingly similar pattern of inhibition appeared, with distamycin A being the more potent. Both drugs showed: A), no inhibitory activity against thymidine kinase and DNA primase; B), low activity against DNA topoisomerases I and 11 and the 3'-5' exonuclease associated with the DNA polymerase e; C), high activity against DNA polymerases a and E, uracil-DNA glycosylase and the joining activity of the replicative DNA ligase; D), the highest inhibitory activity against the AMP-dependent DNA relaxing activity of DNA ligase. The strong in vitro inhibition of several DNA enzymic activities, including DNA ligase, do not match with the in vivo activities of the two drugs. However a unique difference was observed: only FCE24517 inhibited the DNA-independent reaction of adenylation of human DNA ligase while the adenylation reaction of T4 and E. coli DNA ligase was unaffected by either drug. It is still unclear whether these properties are relevant for modulating the killing activity of FCE24517 against proliferating cells both in culture and in vivo. Nevertheless FCE24517 is the first known molecule capable of interacting directly and specifically with human DNA ligase.
British Journal of Cancer, 1999
PNU 151807 is a new synthetic α-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechanism of action of this compound in parallel with the distamycin alkylating derivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in in vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine interact non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as assessed by Taq stop assay and N3 or N7-adenine alkylation assay in different DNA sequences. PNU 151807, like tallimustine, is able to induce an activation of p53, and consequently of p21 and BAX in a human ovarian cancer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compound. Flow cytometric analysis of cells treated with equitoxic concentrations of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time course. When tested against recombinant proteins, only the compound PNU 151807 (and not tallimustine or distamycin A) is able to abolish the in vitro kinase activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes. The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells.
Amino Acids, 2012
Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Distamycin A interactions with Dickerson and Poly[d(AT) 6 ] oligonucleotides show a different thermodynamic with respect to NAX002.
Journal of Biological Chemistry
Saframycin A is an antitumor antibiotic structuraIly characterized by twin heterocyclic quinone skeletons and a-cyanoamine moiety. The binding of saframycin A to DNA was investigated using the antibiotic labeled at different positions. Heterocyclic quinone skeletons were biosynthetically labeled with [14CJtyrosine. The cyano residue of saframycin A was specifically labeled as a result of the reaction of [14C]cyanide with a derivative of saframycins, decyanosaframycin A, in the culture filtrate. When calf thymus DNA was incubated with ['4C]tyrosine-labeled saframycin A in the presence of dithiothreitol, radioactivities were progressively recovered from DNA fraction. In contrast, saframycin A in the absence of dithiothreitol was completely devoid of reactivity toward DNA. When ['4C]cyanide-labeled saframycin A was reacted with DNA, however, none of the radioactivity was associated with DNA. The release of cyano residue from the antibiotic was triggered by the reduction. Thus, conversion of quinone to hydroquinone skeletons as well as conversion of a-cyanoamine to immonium or a-carbinolamine is the consequence of the reduction. The fact that dithiothreitol-inducible binding of saframycin A to DNA was blocked by the addition of excess cyanide indicates that immonium or a-carbinolamine is the actual species involved in the interaction with DNA. The striking similarities between saframycin A and anthramycin in regard to the mode of binding to DNA are discussed.