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We have demonstrated previously that certain members of a series of novel pyrrolo-1,5-benzoxazepine (PBOX) compounds potently induce apoptosis in a variety of human chemotherapy-resistant cancer cell lines and in primary ex vivo material derived from cancer patients. A better understanding of the molecular mechanisms underlying the apoptotic effects of(More)
Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell(More)
In this work, we describe the first application of ligand-based drug design (LBDD) to the derivation of a predictive pharmacophore for the human glucocorticoid receptor (hGR). Creation of a four feature pharmacophore in Catalyst was subsequently validated through a virtual screen of 264000 commercially available compounds. From a selected hit list of 11(More)
We have previously reported that the pro-apoptotic pyrrolobenzoxazepine, PBOX-6, induces apoptosis in chronic myelogenous leukaemia (CML) cells which is accompanied by oligonucleosomal DNA fragmentation. In this study we show that PBOX-6-induced oligonucleosomal DNA fragmentation occurs in the absence of caspase and CAD activation in CML cells. Dissection(More)
The interest in developing synthetic glucocorticoids (GCs) arises from the utility of endogenous steroids as potent anti-inflammatory and immunosuppressant agents. The first GCs to be discovered, such as cortisol or dexamethasone, still represent the main treatment for conditions of the inflammatory process, despite the fact that they carry a significant(More)
SMILES strings and other classic 2D structural formats offer a convenient way to represent molecules as a simplistic connection table, with the inherent advantages of ease of handling and storage. In the context of virtual screening, chemical databases to be screened are often initially represented by canonicalised SMILES strings that can be filtered and(More)
BACKGROUND Endogenous glucocorticoids (GCs) are involved in a range of endocrine functions including the metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as the maintenance of immunological, renal and skeletal homeostasis. There is a need to find agents that preserve the immune effects of GCs without(More)
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