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Nottingham, United Kingdom

Zhang J.,Kunming University of Science and Technology | Stevens M.F.G.,University of Nottingham | Hummersone M.,Pharminox | Madhusudan S.,Academic Unit of Clinical Oncology | And 2 more authors.
Oncology | Year: 2011

Resistance to temozolomide (TMZ), conferred by O6-methylguanine-DNA methyltransferase (MGMT) or mismatch repair (MMR) deficiency, presents obstacles to successful glioblastoma multiforme (GBM) treatment. Activities of novel TMZ analogs, designed to overcome resistance, were tested against isogenic SNB19 and U373 GBM cell lines (V = vector control, low MGMT; M = MGMT overexpression). TMZ and triazene MTIC demonstrated >9-fold resistance in SNB19M cells (cf SNB19V). N-3 methyl ester analog 11 and corresponding triazene 12 inhibited growth of TMZ-sensitive (V) and TMZ-resistant (M) cells (GI50 <50 μM). Ethyl ester 13 and triazene 14 gave similar profiles. MMR-deficient colorectal carcinoma cells, resistant to TMZ (GI50 >500 μM), responded to analog 11 and 13 treatment. Cross-resistance to these agents was not observed in cell lines possessing acquired TMZ resistance (SNB19VR; U373VR). Methyl ester 11 blocked SNB19V, SNB19M and SNB19VR cells in S and G 2/M, causing dose-and time-dependent apoptosis. DNA damage, recruiting excision repair was detected by alkaline comet assay; H2AX phosphorylation indicated a lethal DNA double-strand break formation following analog 11 exposure. Compounds 11 and 13 demonstrated 3.7-and 5.1-fold enhanced activity in base excision repair-deficient Chinese hamster ovary cells; furthermore, poly (ADP-ribose) polymerase-1 inhibition potentiated HCT-116 cells' sensitivity to analog 11. In conclusion, analogs 11 and 13 exert anticancer activity irrespective of MGMT and MMR. © 2011 S. Karger AG, Basel. Source


Capes A.,University of Dundee | Patterson S.,University of Dundee | Wyllie S.,University of Dundee | Hallyburton I.,University of Dundee | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei. © 2011 Elsevier Ltd. All rights reserved. Source


Rizzo A.,Regina Elena Cancer Institute | Iachettini S.,Regina Elena Cancer Institute | Zizza P.,Regina Elena Cancer Institute | Cingolani C.,Regina Elena Cancer Institute | And 7 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2014

The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant β2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off-target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy. © 2014 Rizzo et al.; licensee BioMed Central Ltd. Source


The present invention provides a compound of general formula (II), or a salt or solvate thereof: wherein A is independently -A1, -A2, -A3, -A4, -A5, -A6, or -A7, wherein: -A1 is independently C5-12heteroaryl, and is optionally substituted; -A2 is independently thioamido or substituted thioamido; -A3 is independently imidamido, substituted imidamido, N-hydroxyimidamido, or substituted N-hydroxyimidamido; -A4 is independently hydroxamic acid or hydroxamate; -A5 is independently carboxamide or substituted carboxamide; -A6 is independently aliphatic C2-6alkenyl, and is optionally substituted; and -A7 is independently carboxy or C1-4alkyl-carboxylate;and its use in the synthesis of temozolomide and analogues thereof.


The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid amide (collectively referred to herein as 3TM compounds). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.

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