PHANTAGEN · Photoactivatable platinum(IV)-diazide complexes: a new generation of platinum-based anticancer agents
6РП — Действия „Мария Кюри“
- Период
- 2005-01-01 → 2006-12-31
- Финансиране от ЕС
- 160 180 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Платинени комплекси от четвърти степен на окисление се анализират за това как реагират на светлина и как се свързват с ДНК. Тези процеси помагат за разбирането на механизмите, по които тези съединения могат да действат като средства за борба с рака.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - PHANTAGEN (Photoactivatable platinum(IV)-diazide complexes: a new generation of platinum-based anticancer agents)
We managed to understand the solution properties and possible photoactivation pathways of some photoactivatable Pt(IV)-diazido derivatives, thus providing us with new insights into their mechanism of action as potential anticancer agents. These studies were carried out by means of several spectroscopic techniques including 14N/15N Nuclear magnetic resonance (NMR), [1H,15N] Heteronuclear single quantum correlation or Heteronuclear multiple-bond correlation (HSQC/HMBC) NMR and Electrospray ionisation mass spectrometry (ESI-MS). They proved to be highly challenging, as the peculiarity of the investigated systems presented some obstacles regarding both mapping out the photoreduction pathways and finding the optimal experimental conditions. In particular, 15N NMR methods did not turn out to be as hoped. In order to overcome these problems, we came up with the development and optimisation of different and more suitable analytical techniques to investigate reaction intermediates, major photoproducts and side-products. The optimal experimental conditions, e.g. concentration, temperature, pH, irradiation wavelength and power etc., were investigated in detail. In particular, the use of 14N NMR spectroscopy was shown to be a reliable method to follow the evolution of the investigated compounds upon irradiation, allowing for the identification of both the major photoproducts and the possible photoreduction mechanisms, leading to unexpected and unprecedented results. In addition, the ability of these Pt(IV)-diazido complexes to bind Deoxyribonucleic acid (DNA) under irradiation with both visible and Ultraviolet (UV) light, the binding extent and the identification of the binding sites on nucleobases were successfully investigated, as well as the complexes' binding properties to other biologically-relevant biomolecules. According to our results, two different mechanisms were identified and examined in detail, leading to the conclusion that the photoreaction pathways appeared to be highly dependent on the solution conditions, such as solvent, pH and concentration, and the presence of biomolecules. This study also led to exciting advantages, found in parallel to the main investigation. In fact, this photoactivation strategy seemed to open new perspectives in the creation of compounds whose direct synthesis was not yet achieved.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The ultimate objective of this research work is the preparation and evaluation of novel photoactive platinum(IV)-diazidecomplexes for combating cancer through their photoactivation selectively at the tumour target site. Platinum(II) drugs are now establish ed as effective anti-tumour agents, the archetypal example of these being cisplatin. However, their usefulness is limited by their narrow spectrum of activity (not active enough against several types of cancer), and by the development of acquired resistance after continuous treatment and toxicity (in particular, nephrotoxicity).Thus, several third-generation platinum-based drugs have been prepared and tested, a broad class of these concerning platinum(IV) complexes. Platinum(IV) complexes, compared to their platinum(II) analogues, are extremely inert to substitution reactions and are often more lipophilic. Hence, these complexes have enormous potential as anticancer agents in terms of both high activity and low toxicity, but this potential has not been realized by the drugs investigated to date.This research project is concerned with the synthesis and characterization of new platinum(IV)-diam(m)inediazide derivatives to be evaluated as photoactivatable pro-drugs; in practice, this original approach is intended to facilitate the intra-tumoural activation of platinum(IV)-diam(m)ine derivatives by illumination with visible light to form photolysis products (platinum(II)-diam(m)ine analogues) that irreversibly bind to DNA and are cytotoxic to human cancer cells.This photoactivation strategy should be generally applicable to platinum(IV)-diazide complexes containing a variety of monodentate amino and chelated diamino ligands. The enormous potential impact of this new class of platinum(IV) photochemotherapeutic agent s relies in their site-specific delivery of a wide range of platinum(II)-diam(m)ine drugs in localized cancers strongly improving their cellular uptake and minimizing unwanted side effects.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITY OF EDINBURGH · EDINBURGHКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз