Mark Searcey

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Laurence H. Patterson18
Lesley A Howell13
Klaus Pors12
Maria A. O'Connell10
Paul M. Loadman10
18Laurence H. Patterson
15Klaus Pors
13Lesley A Howell
12Maria A. O'Connell
10Helen M. Sheldrake

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Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is increasingly recognized as a central regulator of multiple signaling pathways in inflammation and cancer, and the ability to use chemical biological tools to investigate its biological effects is very attractive. A peptide comprising a TAT-conjugated Nrf2 sequence is shown to activate Nrf2 and its… (More)
Synthesis of distamycin A polyamides targeting G-quadruplex DNA.
A number of amide-linked oligopyrroles based on distamycin molecules have been synthesized by solid-state methods, and their interactions with a human intramolecular G-quadruplex have been measured by a melting procedure. Several of these molecules show an enhanced ratio of quadruplex vs. duplex DNA binding compared to distamycin itself, including one with… (More)
Synthesis of DNA-directed pyrrolidinyl and piperidinyl confined alkylating chloroalkylaminoanthraquinones: potential for development of tumor-selective N-oxides.
A novel series of 1,4-disubstituted chloroethylaminoanthraquinones, containing alkylating chloroethylamino functionalities as part of a rigid piperidinyl or pyrrolidinyl ring-system, have been prepared. The target compounds were prepared by ipso-displacement of halides of various anthraquinone chromophores by either hydroxylated or chlorinated piperidinyl-… (More)
Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder.
We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer… (More)
Resistance in cancer: a target for drug discovery.
Resistance remains a major problem in the clinical utility of cancer chemotherapy. However, it also represents a tumour cell phenotype that is in many ways different, and thus distinguishable, from the majority of normal cells. Two approaches to the targeting of resistant cells are described involving intratumoral P450 expression, mechanisms of drug-efflux… (More)
Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies.
Echinomycin is the prototypical bisintercalator, a molecule that binds to DNA by inserting two planar chromophores between the base-pairs of duplex DNA, placing its cyclic depsipeptide backbone in the minor groove. As such, it has been the focus of an extensive number of investigations into its biological activity, nucleic acid binding and, to some extent,… (More)
The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53-mDM2 protein-protein interaction.
Inhibitors of key protein-protein interactions are emerging as exciting therapeutic targets for the treatment of cancer. One such interaction between MDM2 (HDM2) and p53, that silences the tumour suppression activities of p53, was found to be inhibited by the recently isolated natural product chlorofusin. Synthetic studies on this complex natural product… (More)
Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity.
The identification of an agent that is selectively activated by a cytochrome P450 (CYP) has the potential for tissue specific dose intensification as a means of significantly improving its therapeutic value. Towards this goal, we disclose evidence for the pathway of activation of a duocarmycin analogue, ICT2700, which targets CYP1A1 for biological activity.
DNA binding by analogues of the bifunctional intercalator TANDEM.
We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the… (More)