Summary: |
Cisplatin is one of the most widely used antineoplastic compounds, since its serendipitous discovery in the 1960´s. However, its
severe side effects and acquired resistance have led to an intense search for new generation Pt(II) and Pd(II) agents, aiming at an
improved cytotoxic profile coupled to a lower toxicity. Polynuclear chelates with polyamines (PAs) as bridging ligands are one such
group of compounds, known to act through covalent binding to DNA (their main pharmacological target), through an interplay not
available to conventional Pt-drugs that leads to an enhanced antineoplastic effect. Nevertheless, the exact nature of the
mechanisms involved, at a molecular level, is still unknown, thus highlighting the relevance of relating structure and conformational
preferences of this kind of systems to their antitumour activity and biochemical impact.
The PI and several partners of the present team (QFM-UC) have long been involved in the study of cisplatin-like Pt and Pd
polynuclear complexes with aliphatic amines (including putrescine, spermidine and spermine, also previously investigated by the
team), aiming at their thorough conformational characterisation and evaluation of anticancer activity towards human neoplastic cell
lines. This work has been developed within several funded R&D projects: PBIC/C/QUI/2219/95 (JNICT, Portugal, LABC as PI);
POCTI/33199/QUI/00 (MPM as PI), POCTI/QUI/47256/2002 (MPM as PI), PTDC/QUI/66701/2006 (MPM as PI); POCI/SAUBEB/
66896/2006 (FCT, Portugal); European COST Actions 922 and BM1401 (http://bit.ly/1vTAp8A); EU/IHP Programme for ISIS
Neutrons (MPM and LABC group leaders). Reliable Structure-Activity Relationships (SAR´s) were established for these systems and
quite promising results have been obtained for a Pd(II) agent [1]. The present project thus comes as a natural follower of this line
of research, with a view to extend the information available on the metal chelates to their pharmacokinetic and ph |
Summary
Cisplatin is one of the most widely used antineoplastic compounds, since its serendipitous discovery in the 1960´s. However, its
severe side effects and acquired resistance have led to an intense search for new generation Pt(II) and Pd(II) agents, aiming at an
improved cytotoxic profile coupled to a lower toxicity. Polynuclear chelates with polyamines (PAs) as bridging ligands are one such
group of compounds, known to act through covalent binding to DNA (their main pharmacological target), through an interplay not
available to conventional Pt-drugs that leads to an enhanced antineoplastic effect. Nevertheless, the exact nature of the
mechanisms involved, at a molecular level, is still unknown, thus highlighting the relevance of relating structure and conformational
preferences of this kind of systems to their antitumour activity and biochemical impact.
The PI and several partners of the present team (QFM-UC) have long been involved in the study of cisplatin-like Pt and Pd
polynuclear complexes with aliphatic amines (including putrescine, spermidine and spermine, also previously investigated by the
team), aiming at their thorough conformational characterisation and evaluation of anticancer activity towards human neoplastic cell
lines. This work has been developed within several funded R&D projects: PBIC/C/QUI/2219/95 (JNICT, Portugal, LABC as PI);
POCTI/33199/QUI/00 (MPM as PI), POCTI/QUI/47256/2002 (MPM as PI), PTDC/QUI/66701/2006 (MPM as PI); POCI/SAUBEB/
66896/2006 (FCT, Portugal); European COST Actions 922 and BM1401 (http://bit.ly/1vTAp8A); EU/IHP Programme for ISIS
Neutrons (MPM and LABC group leaders). Reliable Structure-Activity Relationships (SAR´s) were established for these systems and
quite promising results have been obtained for a Pd(II) agent [1]. The present project thus comes as a natural follower of this line
of research, with a view to extend the information available on the metal chelates to their pharmacokinetic and pharmacodynamic
profiles, particularly regarding: (i) cellular and tissue bioavailability; (ii) cyto- and histological effects; (iii) induced metabolic
changes.
Accordingly, several methodologies are chosen as the most suitable for attaining the proposed goals (Fig. 1): (i) Vibrational
spectroscopy (Raman, Fourier Transform Infrared (FTIR), Inelastic Neutron Scattering (INS)) and synchrotron-based Extended X-ray
Absorption Fine Structure (EXAFS), for a thorough characterisation of the metal´s coordination pattern and the conformational
preferences of the complexes and their DNA adducts. (ii) Quantification of the intracellular complex concentration by LC-MS/MS
(liquid chromatography/tandem mass spectrometry), and bioavailability assessment by atomic absorption and scintillation counting
methods. (iii) Raman microspectroscopy and synchrotron radiation infrared microspectroscopy (SR-IRMS), yielding 3D-chemical
images of living cells, for monitoring biodistribution and metabolic changes. These are state-of-the-art techniques for obtaining high
resolution information at the cellular (and sub-cellular) level, particularly useful for cyto- and histopatological analysis upon drug
administration. (iv) 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR) spectroscopy, to assess
the impact of the chelates on intracellular metabolism, followed by cell extracts analysis by liquid state 1H and 31P-NMR. NMR
characterisation of selected chelate/cell line combinations will yield specific information on the changing metabolites. (v) Studies on
the effect of the antineoplastic compounds on intra |