For the synthesis and selection of active platinum-based anticancer drugs that perform better than cisplatin and its analogues, six-coordinate octahedral Pt(IV) complexes appear to be promising candidates as, being kinetically more inert and more resistant to ligand substitution than four-coordinate Pt(II) centers, they are able to minimize unwanted side reactions with biomolecules prior to DNA binding. Due to their kinetic inertness, Pt(IV) complexes have also been exploited to bypass inconvenient intravenous administration. The most prominent example is satraplatin (Sat.) which is the first platinum antineoplastic agent reported to have oral activity. The present paper deals with a theoretical DFT investigation of the influence that the acidity of the biological environment can have on the activity of satraplatin and analogous octahedral Pt(IV) complexes having two carboxylates as axial ligands. Moreover, here the outcomes of a joint electrospray ionization mass spectrometry and DFT investigation of the fragmentation pathways of the protonated satraplatin are reported. Calculations show that the simulated acidic environment has an important impact on the satraplatin reactivity causing a significant lowering of the barrier that is necessary to overcome for the hydrolysis of the first acetate ligand to occur. Data from electrospray ionization mass spectrometry, H NMR, and potentiometric experiments strongly suggest that the loss of CHCOOH from the protonated satraplatin ion [Sat. + H] takes place almost immediately upon dissolution of satraplatin in methanol-water, DO, and water solutions, respectively, at room temperature.
Macromolecules including macrocyclic species have been reported to have the potential to encapsulate biologically active compounds such as drugs through host-guest complexation to increase their solubility, stability and bioavailability. Here we investigate the complexation between nedaplatin, a second generation antineoplastic drug, and p-4-sulfocalix[4]arene, a macromolecule possessing a bipolar amphiphilic structure with good biocompatibility and relatively low haemolytic toxicity for potential use as a drug delivery system. Data from 1H NMR, UV-Vis spectroscopy, Job’s plot analysis, HPLC, DSC and DFT calculations are detailed and suggest the formation of a 1:1 complex. The stability constant of the complex was experimentally estimated to be 3.6 × 104 M−1 and 2.1 × 104 M−1 which correspond to values of −6.2 and −5.9 kcal mol−1, respectively for the free energy of complexation while the interaction free energy is calculated to be −4.9 kcal mol−1. The formed species is shown to be stabilised in solution through hydrogen bonding between the host and the guest. The complex displayed enhanced antitumor activity against MDA-MB-231 cells compared to nedaplatin which may allow for its application in cancer therapy.
“Green
analytical chemistry” (GAC) is a vital area towards the concept
of sustainability. As a consequence of the widespread application
of HPLC in drug-related analytical investigations and the resulting
contamination of the environment with organic solvents questions have
been raised about the toxicity/greenness of HPLC in the ecosystem.
Traditional analytical separation technologies yield approximately
50 mL of waste per analytical data point. To this end, the pharmaceutical
community continues to search for greener opportunities to markedly
reduce the amount of organic waste produced and move from conventional
offline separation based methodologies to greener in-line alternatives. In this contribution, we’re adopting a “Just-Dip-It”
approach with the ultimate goal of advancing and exploiting the potentiometric
sensors to their most effective use in different disciplines of drug
development. The unique abilities of these ion-selective electrodes
(ISEs) for in-line measurements is the key driver for adoption of
GAC principles to improve environmental friendliness of the analytical
methods. For a meaningful comparison, this work compares the organic
waste resulting from ISEs versus HPLC for degradation kinetics monitoring
of active pharmaceutical ingredients (APIs) with respect to the 12
principles of GAC. Ipratropium bromide (IP) was chosen as a hydrolyzable
anticholinergic drug, and its degradation kinetics were monitored
by the two techniques. The first in-line strategy is attained by dipping
a highly integrated IP membrane sensor for continuous monitoring of
the hydrolysis kinetics of IP by tracing the emf decline over the
time scale. The second off-line strategy utilizes a separation-based
chromatographic HPLC method via discontinuous tracking the decrease
of IP peak area spectroscopically at 220 nm over time. The advantages
and shortcomings of each strategy considering GAC principles are highlighted.
The merits of these benign real-time analyzers (ISEs) that can deliver
equivalent analytical results as HPLC while significantly reducing
solvent consumption/waste generation are described. Finally, an applicable
strategy for expansion of the Just-Dip-It approach to different disciplines
of drug-related analytical investigations is addressed.
Host–guest complexation between SUC with p-sulfonatocalix[4]arene. Supramolecular complex characterization by UV & NMR spectroscopy. First spectrophotometric method for SUC determination.
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