Cytotoxic α-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety (original) (raw)
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Bioorganic & Medicinal Chemistry, 2003
The design, synthesis and in vitro activities of novel a-bromoacryloyl pyrazole, imidazole and benzoheterocyclic derivatives of distamycin A, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed. In spite of the relevance of these modifications on the distamycin frame, these derivatives showed significant growth inhibitory activity against mouse leukemia L1210 cells. Therefore, the presence of the amidino moiety, and in general of a basic moiety, is not an absolute requirement for biological activity of a-bromoacrylic derivatives of distamycin. #
Cytotoxic halogenoacrylic derivatives of distamycin A
Bioorganic & Medicinal Chemistry Letters, 2000
ÐThe design, synthesis, in vitro and in vivo activities of a series of halogenoacrylic derivatives of distamycin A are described. The structure±activity relationships indicate a key role of the reactivity of a-halogenoacrylic moiety. The reactivity and the putative alkylating mechanism of these compounds are dierent from those of the nitrogen mustards and possibly based on a Michael type reaction. This supports the hypothesis that these compounds represent a class of minor groove binders mechanistically dierent from tallimustine.
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.
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.
International journal of molecular medicine, 2009
Derivatives of distamycin A modified at the C-terminal amidine moiety and tethered to bis-epoxyethyl moieties at the N-terminal position were tested for their ability to induce erythroid differentiation in the human erythroleukemic cell line K562. None of the compounds without bis-epoxyethyl moiety were active. A comparison of the biological activity of diepoxy compounds containing different non-basic amidine-modified moieties, showed low activity of amidoxime, carbamoyl and N-methyl carbamoyl derivatives as differentiation agents. In contrast, a cyanamidine derivative, compound 3, was able to induce erythroid differentiation of K562 cells. In addition, the cyanamidine derivative 3 was able to induce HbF accumulation following treatment of cultures of erythroid precursor cells isolated from the peripheral blood of normal subjects.
Biological activity and DNA Sequence Specificity of Synthetic Carbamoyl Analogues of Distamycin
Antiviral Chemistry and Chemotherapy, 1997
A new penta(N-methylpyrrole carboxamide) analogue of the antibiotic distamycin has been synthesized in which the N-terminal formylamino group was replaced by a carbamoyl moiety. It was substantially more stable than distamycin in aqueous solution and bound to DNA with about the same affinity constant. It had an exemplary margin of selectivity against herpes simplex virus type 1-infected HEp-2 cells in culture compared to uninfected control cells, and was equipotent with distamycin. For comparison, data for analogues containing fewer N-methylpyrrole carboxamide units and/or lacking the carbamoyl replacement are presented. Extensive DNase I footprinting experiments were conducted and revealed that all the distamycin analogues bound to AT-rich nucleotide sequences in three different restriction fragments, irrespective of how many pyrrole rings or which terminal moiety they contained. However, the relative strength of footprints differed significantly among the various compounds, though...
Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20‐oxo Analogues
ChemMedChem, 2019
The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double‐modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single‐ [N,N‐dipropyl amide of salinomycin (5 a)] and two novel double‐modified analogues [N,N‐dipropyl amide of C20‐oxosalinomycin (5 b) and piperazine amide of C20‐oxosalinomycin (13 b)] were found to be more potent toward the MDA‐MB‐231 cell line than SAL or its C20‐oxo analogue 2. When select analogues were tested against the NCI‐60 human tumor cell line panel, 4 a [N,N‐dieth...