A Strategy for Imidazotetrazine Prodrugs with Anti-cancer Activity Independent of MGMT and MMR

The imidazotetrazine ring is an acid-stable precursor and prodrug of highly-reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of temozolomide

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

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

Business case for mussel aquaculture in offshore wind farms in the North Sea

The European Blue Growth strategy aims to expand the new maritime sectors of aquaculture, energy, biotechnology, coastal tourism and mineral mining. Growth of these sectors will increases pressure on the seas, particularly on those areas that are densely used by traditional sectors such as fisheries and transport. This has triggered interest in developing multiuse of space and multiuse platforms at sea. This paper assesses the feasibility of offshore mussel production project in wind farms by design and ex-ante evaluation of a mussel aquaculture system in the North Sea. A system for mussel cultivation in the Dutch Borssele offshore wind farm was designed, producing both mussel seed and consumption-sized mussels with semi-submerged longlines. Based on the economic model and the risk assessment, this paper concludes that mussel aquaculture is an appealing commercial model for increased returns in offshore wind farms. The economic models shows that the internal rate of return and net present value are positive and based on the sensitivity analysis, it can be concluded that these results are robust