Anticancer Mutual Prodrugs Activated by Hypoxia

The effectiveness of current anticancer drugs such as nitrogen mustards, 5-fluorouracil and sunitinib is hampered by dose-limiting side effects. Targeted prodrugs designed to be selectively activated in hypoxic regions of solid tumours and locally deliver active cytotoxins are potentially very useful for improving the efficacy and side effect profiles of anticancer chemotherapeutics. This project investigated rationally designed hypoxiaactivated antitumour amide- and ester-linked kinase inhibitor–cytotoxin prodrug conjugates. These mutual prodrugs combined an angiogenesis inhibitor, semaxanib (SU5416), together with a cytotoxin into a single molecule, with the cytotoxin being either a 4-aminoaniline nitrogen mustard or floxuridine (an FDA-approved antimetabolite). The compounds contained an arylnitro triggering group designed to undergo bioreductive activation selectively in hypoxic regions of tumours to the aniline derivative. Formation of the aniline group then initiates a spontaneous intramolecular cyclisation reaction to simultaneously eject the two active anticancer drugs. The first goal of the project was to devise and implement viable synthetic routes towards semaxanib|4-aminoaniline mutual prodrug 1 and semaxanib|floxuridine mutual prodrug 2. The synthesis of mutual prodrug 1 was optimised and scaled-up based on a previous small-scale synthesis completed by PhD student Nicholas Kirk. The synthesis of 1 was accomplished in 6 steps providing 190 mg of 1 prepared in pure form. The synthesis of mutual prodrug 2 was completed in 7 steps to give a total of 302 mg of pure 2

Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen

2-Aryl isatogens and their 3-imino derivatives have been extensively studied but to date there have been no reported variants carrying pyrrolyl substituents at the 2-position. This study describes the unexpected synthesis of two novel 3-imino-2-(pyrrol-2-yl) isatogen derivatives upon attempted amide couplings with (E)- or (Z)-3-(3,5-dimethyl-1H-pyrrol-2-yl)-2-(2-nitrophenyl)acrylic acids and p-phenylenediamines in the presence of uronium-based coupling reagents. Imine hydrolysis of one derivative under mild acid conditions afforded a 2-pyrrolyl isatogen in high yield. The compound showed potent in vitro antiplasmodial activity against Plasmodium falciparumN. Kirk and G. Sansom acknowledge financial support from the Australian Government for Australian Postgraduate Awards. P. Sudta and S. Suksamrarn acknowledge financial support from the Thailand Research Fund through the Royal Golden Jubilee PhD Program. M. Kelso acknowledges partial financial support from the University of Wollongong

Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen

<p>2-Aryl isatogens and their 3-imino derivatives have been extensively studied but to date there have been no reported variants carrying pyrrolyl substituents at the 2-position. This study describes the unexpected synthesis of two novel 3-imino-2-(pyrrol-2-yl) isatogen derivatives upon attempted amide couplings with (<i>E</i>)- or (<i>Z</i>)-3-(3,5-dimethyl-1<i>H</i>-pyrrol-2-yl)-2-(2-nitrophenyl)acrylic acids and <i>p</i>-phenylenediamines in the presence of uronium-based coupling reagents. Imine hydrolysis of one derivative under mild acid conditions afforded a 2-pyrrolyl isatogen in high yield. The compound showed potent in vitro antiplasmodial activity against <i>Plasmodium falciparum.</i></p

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin