UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A

Baraldi, PG; Romagnoli, R; Guadix, AE; de las Infantas, MJP; Gallo, MA; Espinosa, A; Martinez, A; ... Hartley, JA; + view all (2002) Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A. J MED CHEM , 45 (17) 3630 - 3638. 10.1021/jm011113b.

Full text not available from this repository.

Abstract

The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a molecular combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliphatic carboxylic acid moieties containing a flexible polymethylene chain that is variable in length [(CH2)(n), where n = 1-6). All the hybrid compounds in this series exhibit enhanced activity compared to both distamycin A and uramustine derivatives 22-27 used for conjugation, giving IC50 values in the range 7.26-0.07 muM following a 1 h exposure of human leukemic K562 cells, with maximal activity shown when n = 6. The distance between the uramustine and distamycin frame is crucial for the cytotoxicity, with compounds having linker lengths of four to six being at least 20-fold more cytotoxic than liker lengths one to three. Taq polymerase stop experiments demonstrated selective covalent binding of uramustine-distamycin hybrids to A/T rich DNA sequences, which was again more efficent with compounds 32-34 with a longer linker length. Two consequences can be derived from our study: (a) the distamycin moiety directs binding to the minor groove of A/T rich DNA sequences and, consequently, is responsible for the alkylation regioselectivity found in footprinting studies; (b) the higher flexibility due to a longer linker between the distamycin and uracil moieties allows the formation of complexes with the mustard moiety situated more deeply in the minor groove and, hence, with better alkylating properties.

Type: Article
Title: Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A
DOI: 10.1021/jm011113b
Keywords: SEQUENCE SPECIFICITY, IN-VITRO, GUANINE-N7 ALKYLATION, CYTOTOXIC PROPERTIES, NITROGEN MUSTARDS, BINDING LIGANDS, URACIL MUSTARD, BASE-PAIRS, MOLECULES, PYRROLO<2,1-C><1,4>BENZODIAZEPINE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/108988
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item