34 research outputs found

    Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53.

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    The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed

    Parameters affecting water-hammer wave attenuation, shape and timing. Part 2: Case studies

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    This two-part paper investigates parameters that may significantly affect water-hammer wave attenuation, shape and timing. Possible sources that may affect the waveform predicted by classical water-hammer theory include unsteady friction, cavitation (including column separation and trapped air pockets), a number of fluid–structure interaction effects, viscoelastic behaviour of the pipe-wall material, leakages and blockages. Part 1 of this two-part paper presents the mathematical tools needed to model these sources. Part 2 of the paper presents a number of case studies showing how these modelled sources affect pressure traces in a simple reservoir-pipeline-valve system. Each case study compares the obtained results with the standard (classical) water-hammer model, from which conclusions are drawn concerning the transient behaviour of real systems.Anton Bergant, Arris S. Tijsseling, John P. Vítkovský, Dídia I. C. Covas, Angus R. Simpson and Martin F. Lamber
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