Synthesis and growth inhibition activity of α-Bromoacrylic heterocyclic and benzoheterocyclic derivatives of distamycin A modified on the amidino moiety (original) (raw)

Cytotoxic α-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety

Bioorganic & Medicinal Chemistry Letters, 2000

ÐThe design, synthesis, in vitro and in vivo activities of novel a-bromoacrylic derivatives of distamycin A, modi®ed at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modi®cations of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore, not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development.

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.

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.

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...