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604 records · Page 34Linked to original sources
PubMed1993

DNA sequence-selective binding of head-to-tail linked bis-lexitropsins: relation of phasing to cytotoxic potency.

A series of polymethylene, -(CH2)n-tether-linked head-to-tail bislexitropsins (n = 1-7) have been synthesized in order to assess the effect on DNA binding of phasing, that arises because of lack of dimensional correspondence between oligopeptides and oligonucleotides. Binding constants to poly(dA-dT), estimated from ethidium displacement, are from 0.55 to 16.66 x 10(8) M-1. Comparable Ka values for calf thymus DNA and for poly(dG-dC) are approximately 10(6) and approximately 10(5) M-1, respectively reflecting the anticipated AT preference. Sequence-selective binding was examined by reflecting the anticipated AT preference. Sequence-selective binding was examined by methylethidium propyl ethylenediamine tetraacetic acid (MPE) complementary strand footprinting on an EcoRI/HindIII restriction fragment of pBR322 DNA with r = 0.08 and 0.32. Ligands bearing N-methylpyrrole dipeptide moieties linked by -(CH2)n, where n = 2, 4 or 6, give evidence of bidentate binding in (AT)n-rich sequences from footprinting at r = 0.32. By contrast, those ligands linked by (CH2)n, where n = 1, 3, 5 or 7, bind in a predominantly monodentate fashion. Cystostatic activity against KB human nasopharyngeal cancer cells has shown enhanced potency, compared with distamycin, for those linked bis-lexitropsins with n = 2, 4 and 6. That the increased potency may be attributed to more effective DNA binding in the latter cases is indicated by the fact that the n = 1, 3, 5 and 7 ligand homologues do not exhibit comparable enhanced cytotoxic potency.

Antineoplastic Agents↗
PubMed1996

Design, synthesis and topoisomerase II inhibition activity of 4'-demethylepipodophyllotoxin-lexitropsin conjugates.

The design and synthesis of 4'-demethylepipodophyllotoxin-lexitropsin conjugates capable of inhibiting the actions of topoisomerase II are described. Siteselective topoisomerase II cleavage was observed in the presence of the new inhibitors, as determined by DNA sequencing. Additional topoisomerase II cleavage sites were observed with the new compounds that seem to be characteristic of the minor groove-binding lexitropsin moieties. Compound 17, having three pyrrole units in its binding moiety, exhibited distinct topoisomerase-mediated sites of cleavage at positions 4258, 4257, 4255 and 4247 of the pBR322 DNA fragment. These results demonstrate that conjugation with minor groove-binding moieties can alter or increase the number of topoisomerase II-induced cleavable sites and contribute to our understanding of the cytostatic activity of these compounds against KB cancer cell lines.

Antineoplastic Agents↗
PubMed1996

Novel DNA-directed alkylating agents consisting of naphthalimide, nitrogen mustard and lexitropsin moieties: synthesis, DNA sequence specificity and biological evaluation.

Novel DNA-directed alkylating agents comprising naphthalimide, nitrogen mustard and lexitropsin moieties have been designed, synthesized and characterized. Their properties have been evaluated with respect to DNA binding ability, sequence preference, influence of flanking sequences on alkylation efficiency and cytotoxic potency against KB human nasopharangeal tumour cells. The results indicate that, in contrast to distamycin and bis-benzimidazole-bearing nitrogen mustard moieties where DNA alkylation is directed to adenine N3 sites in the minor groove, the naphthalimide nitrogen mustards alkylate DNA at accessible guanine N7 sites within the major groove. Structural factors that may affect cytotoxic efficacy are discussed.

1-Naphthylamine↗
PubMed1997

Enediyne-lexitropsin DNA-targeted anticancer agents. Physicochemical and cytotoxic properties in human neoplastic cells in vitro, and intracellular distribution.

Two series of hybrids of a dynemicin A model and DNA minor groove binding lexitropsins were synthesized and their cytotoxic activities were investigated in a panel of human normal and malignant cell lines using a colorimetric assay. Adriamycin was used as a control. Several of the agents demonstrated cytotoxic activity, the extent of which varied with tumor type. IC50s of the hybrids ranged from approximately 14-48 microM following 96 h incubation in the presence of test compound. Intracellular distribution studies were facilitated through endogenous fluorescence of the compounds. Evidence of nuclear uptake of the hybrid agents was demonstrated by confocal laser scanning microscopy. The results warrant further development of DNA-targeted enediyne-lexitropsin hybrids as potential anticancer agents.

Antibiotics, Antineoplastic↗
PubMed1999

N-(2-chloroethyl)-N-nitrosourea tethered to lexitropsin induces minor groove lesions at the p53 cDNA that are more cytotoxic than mutagenic.

Many different N-chloroethyl-N-nitrosourea (CENU) derivatives have been synthesized in an attempt to minimize carcinogenic activity while favoring antineoplastic activity. CENU derivatives linked to the dipeptide lexitropsin (lex) showed significant changes in groove- and sequence-selective DNA alkylation inducing thermolabile N3-alkyladenines (N3-Alkyl-As) at lex equilibrium binding sites. CENU-lex sequence specificity for DNA alkylation was determined using 32P-end-labeled restriction fragments of the p53 cDNA. The adducted sites were converted into single-strand breaks by sequential heating at neutral pH and exposure to piperidine. To establish the mutagenic and lethal properties of CENU-lex-specific lesions, a yeast expression vector harboring a human wild-type p53 cDNA was treated in vitro with CENU-lex and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. p53 mutants were isolated from independent ade- transformants. The results revealed that: (a) CENU-lex preferentially induces N3-Alkyl-A at specific lex equilibrium binding sites, the formations of which are strongly inhibited by distamycin; (b) reactivity toward Gs is still present, albeit to a lesser extent when compared to N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea and to CENU; (c) 91% of the 49 CENU-lex p53 mutations (45 of 49) were bp substitutions, 29 of which were GC-->AT transitions, mainly at 5' purine G sites; (d) all AT-targeted mutations but one were AT-->TA transversions; (e) the distribution of the CENU-lex mutations along the p53 cDNA was not random, with position 273 (codon 91), where only GC-->AT transitions were observed, being a real (n = 3, P < 0.0002) CENU-lex mutation hot spot; and (f) a shift in DNA alkylation sites between lesion spectra induced by CENU-lex and N-(2-chloroethyl-N-cyclohexyl-N-nitrosourea was associated with an increased lethality and a decreased mutagenicity, whereas no dramatic change in mutational specificity was observed. Hence, it is tempting to conclude that, in this experimental system, N3-Alkyl-A is more lethal than mutagenic, whereas O6-alkylguanine is a common premutational lesion formed at non-lex binding sites. These results suggest that CENU derivatives with virtually absolute specificity for A residues would make targeting of lethal, nonmutagenic lesions at A+T-rich regions possible, and this may represent a new strategy for the development of new chemotherapeutic agents with a higher therapeutic index.

Alkylation↗