Wyatt, Michael Dunton; (1996) Molecular pharmacology of a series of nitrogen mustard containing-and AT- and GC- recognising minor groove binding agents related to distamycin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The determination of a structure-activity relationship for a series of minor groove binding agents based on the framework of distamycin and which conjugate an aromatic nitrogen mustard is presented. The nitrogen mustard was either benzoic acid mustard (BAM) or chlorambucil (CHL), and was located on the N-terminus of the lexitropsin. The heterocyclic units for the lexitropsin in each family were either AT-recognising pyrroles or GC- recognising imidazoles. Each family contains conjugates of one, two, and three heterocyclic units. The cytotoxicity, DNA interstrand crosslinking, and DNA sequence specificity of alkylation were determined for the series. With one exception, each conjugate was more cytotoxic than the respective parent nitrogen mustard and the cytotoxicity increased for each increase in the number of heterocyclic units. The BAM conjugates cross-linked isolated DNA poorly, while the CHL conjugates cross-linked DNA more efficiently than CHL. Cross-linking efficiency was not affected by the increase in the number of heterocyclic units. Interstrand cross-link formation in cells agreed with the studies in isolated DNA. The sequence specificity of alkylation for the conjugates was determined using modified sequencing techniques. The CHL conjugates were found to alkylate DNA with a similar sequence specificity to that seen for CHL. The monoheterocyclic-BAM conjugates retained the alkylation pattern of BAM, but additional minor groove sites were alkylated. The di- and triheterocyclic-BAM conjugates only alkylated selected sites in the minor groove and the triheterocyclic- BAM conjugates alkylated a subset of those sites alkylated by the mono- and diheterocyclic conjugates, namely the sequence 5'-TTTTGPu. The BAM conjugates showed the greater increase in cytotoxicity and enhancement in alkylation specificity compared to the parent nitrogen mustard, indicating that the less reactive nitrogen mustard was targeted by the lexitropsin more efficiently. The findings have implications for the design of minor groove agents that conjugate reactive groups.

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