The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CHCOO)Cl(NH)(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake.

The biological behavior of the axially unsymmetric antitumor prodrug (-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), , was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido and diacetato , which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues and .

Pt(IV) antitumor prodrugs: dogmas, paradigms, and realities.

Platinum(II)-based drugs are widely used for the treatment of solid tumors, especially in combination protocols. Severe side effects and occurrence of resistance are the major limitations to their clinical use. To overcome these drawbacks, a plethora of Pt(IV) derivatives, acting as anticancer prodrugs, have been designed, synthesized and preclinically (often only ) tested.

Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines.

Cisplatin is widely employed as a first-line chemotherapeutic agent for many solid tumors, including malignant pleural mesothelioma (MPM). However, its clinical use is limited by heavy side effects and acquired resistance, the latter being mainly related to enhanced DNA repair. Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPis) have been carried out, with the hope that such combinations might lead to improved therapeutic efficacy against tumors.

Can the Self-Assembling of Dicarboxylate Pt(IV) Prodrugs Influence Their Cell Uptake?

The possibility of spontaneous self-assembly of dicarboxylato Pt(IV) prodrugs and the consequences on their uptake in cancer cells have been evaluated in different aqueous solutions. Four Pt(IV) complexes, namely, (OC-6-33)-diacetatodiamminedichloridoplatinum(IV), , (-6-33)-diamminedibutanoatodichloridoplatinum(IV), , (-6-33)-diamminedichloridodihexanoatoplatinum(IV), , and (-6-33)-diamminedichloridodioctanoatoplatinum(IV), , have been dispersed in i) milliQ water, ii) phosphate buffered saline, and iii) complete cell culture media (RPMI 1640 or DMEM) containing fetal bovine serum (FBS). The samples have been analyzed by dynamic light scattering (DLS) to measure the size and distribution of the nanoparticles possibly present.

Cis,cis,trans-[PtCl(NH)(perillato)], a dual-action prodrug with excellent cytotoxic and antimetastatic activity.

Two Pt(iv) conjugates containing one or two molecules of perillic acid (4-isopropenylcyclohexene-1-carboxylic acid), an active metabolite of limonene, were synthesized both with traditional and microwave-assisted methods and characterized. Their antiproliferative activity was tested on a panel of human tumor cell lines. In particular, cis,cis,trans-[PtCl(NH)(perillato)] exhibited excellent antiproliferative and antimetastatic activity on A-549 lung tumor cells at nanomolar concentrations.

Can an Elusive Platinum(III) Oxidation State be Exposed in an Isolated Complex?

Platinum(IV) complexes are extensively studied for their activity against cancer cells as potential substitutes for the widely used platinum(II) drugs. Pt complexes are kinetically inert and need to be reduced to Pt species to play their pharmacological action, thus acting as prodrugs. The mechanism of the reduction step inside the cell is however still largely unknown.

A multi-methodological inquiry of the behavior of cisplatin-based Pt(IV) derivatives in the presence of bioreductants with a focus on the isolated encounter complexes.

The study of Pt(IV) antitumor prodrugs able to circumvent some drawbacks of the conventional Pt(II) chemotherapeutics is the focus of a lot of attention. This paper reports a thorough study based on experimental methods (reduction kinetics, electrochemistry, tandem mass spectrometry and IR ion spectroscopy) and quantum-mechanical DFT calculations on the reduction mechanism of cisplatin-based Pt(IV) derivatives having two hydroxido (1), one hydroxido and one acetato (2), or two acetato ligands (3) in axial position. The biological reductants glutathione and ascorbic acid were taken into consideration.

New Platinum-Based Prodrug Pt(IV)Ac-POA: Antitumour Effects in Rat C6 Glioblastoma Cells.

Gliomas are the most frequent primary tumours of the nervous system, characterised by high degree of malignancy, widespread invasion and high-rate proliferation. Cisplatin and analogue are currently employed in clinical trials as active chemotherapeutic agents for the systemic treatment of this type of malignancy. Despite therapy benefits, clinical use of these agents is hampered by severe side effects including neurotoxicity.

Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen .

Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conjugates that in turn promotes increased cellular accumulation.

Elusive Intermediates in the Breakdown Reactivity Patterns of Prodrug Platinum(IV) Complexes.

Kinetically inert platinum(IV) complexes are receiving growing attention as promising candidates in the effort to develop safe and valid alternatives to classical square-planar Pt(II) complexes currently used in antineoplastic therapy. Their antiproliferative activity requires intracellular Pt(IV)-Pt(II) reduction (activation by reduction). In the present work, a set of five Pt(IV) complexes has been assayed using mass spectrometry-based techniques, i.

Pt(IV) Bifunctional Prodrug Containing 2-(2-Propynyl)octanoato Axial Ligand: Induction of Immunogenic Cell Death on Colon Cancer.

The synthesis, characterization, and in vitro activity of a cyclohexane-1 R,2 R-diamine-based Pt(IV) derivative containing the histone deacetylase inhibitor rac-2-(2-propynyl)octanoato, namely, ( OC-6-44)-acetatodichlorido(cyclohexane-1 R,2 R-diamine)( rac-2-(2-propynyl)octanoato)platinum(IV), are reported together with those of its isomers containing enantiomerically enriched axial ligands. These Pt(IV) complexes showed comparable activity, of 2 orders of magnitude higher than reference drug oxaliplatin on three human (HCT 116, SW480, and HT-29) and one mouse (CT26) colon cancer cell lines. In vivo experiments were carried out on immunocompetent BALB/c mice bearing the same syngeneic tumor.

Wine evolution during bottle aging, studied by H NMR spectroscopy and multivariate statistical analysis.

The study of wine evolution during bottle aging is an important aspect of wine quality. Ten different red wines (Vitis vinifera) from Piedmont region were analysed 3 months after bottling and after a further 48 month conservation in a climate controlled wine cellar kept at a constant/controlled temperature of 12 °C. Two white wines (Vitis vinifera) were included in this study for comparison purposes.

Hybrid inorganic (nonporous silica)/organic (alginate) core-shell platform for targeting a cisplatin-based Pt(IV) anticancer prodrug.

Nonporous silica nanoparticles with an external shell containing the 3‑aminopropyl arm (SiNP) were further decorated with alginic acid (SiNP-ALG) as a potential biocompatible delivery system for Pt antitumor agents. Such particles were coupled with the prodrug (OC‑6‑44)‑acetato(β‑alaninato)diamminedichloridoplatinum(IV), 1, through the formation of amide bonds between the pendant carboxylate groups on SiNP-ALG and the free amino group of the complex. Cytosol extracted from tumor cells was able to quickly and efficiently reduce the Pt(IV) prodrug, and produces the active metabolite cisplatin.

Isolation and characterization of a photosystem II preparation from thylakoid membranes of the extreme halophyte Salicornia veneta Pignatti et Lausi.

Salicornia veneta (Pignatti et Lausi) is an extreme halophyte living in salt marsh where NaCl concentration may be as high as 1 M. Here we report on the isolation and characterization of a PSII preparation obtained by Triton X-100 solubilisation of the thylakoid membrane. By a combination of gel electrophoresis, immunoblotting and mass spectrometry, the depletion of a number of PSII proteins such as PsbQ, PsbM and PsbT was highlighted.

A new platinum-based prodrug candidate: Its anticancer effects in B50 neuroblastoma rat cells.

Aims: Neuroblastoma is a rare cancer that affects children, mostly under the age of 5. This type of cancer starts in very early forms of immature nerve cells or developing cells found in embryo or fetus. To date cisplatin represents one of the most potent antitumor agent known, however, the onset of systemic side effects and the induction of drug resistance limit its use in the clinic for long-term treatment.

The cisplatin-based Pt(iv)-diclorofibrato multi-action anticancer prodrug exhibits excellent performances also under hypoxic conditions.

Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance.

An unsymmetric cisplatin-based Pt(iv) derivative containing 2-(2-propynyl)octanoate: a very efficient multi-action antitumor prodrug candidate.

The design, synthesis, characterization and biological properties of a Pt(iv) complex containing the very active inhibitor of histone deacetylase (2-propynyl)octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(iv), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato)platinum(iv), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid.

JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells.

Background: Malignant Pleural Mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance-associated c-Myc and Fra-1.

Objective: We investigated if JQ1 could enhance the efficacy of cisplatin against MPM.

Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates.

We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH)Cl(OA)] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity.

May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?

A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion.

Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes.

Phenanthriplatin, that is, (-4-3)-diamminechlorido(phenanthridine)platinum(II) nitrate, an effective antitumor cationic Pt(II) complex, was loaded on negatively charged dextran sulfate () as a model vector for drug delivery electrostatic interactions. The free complex and the corresponding conjugate with were tested on two standard human tumor cell lines, namely, ovarian A2780 and colon HCT 116, and on several malignant pleural mesothelioma cell lines (namely, epithelioid BR95, mixed/biphasic MG06, sarcomatoid MM98, and sarcomatoid cisplatin-resistant MM98R). The results suggest that the conjugate releases the active metabolite phenanthriplatin with a biphasic fashion.

Antiproliferative activity of a series of cisplatin-based Pt(IV)-acetylamido/carboxylato prodrugs.

We report studies of a novel series of Pt(IV) complexes exhibiting an asymmetric combination of acetylamido and carboxylato ligands in the axial positions. We demonstrate efficient synthesis of a series of analogues, differing in the alkyl chain length and hence lipophilicity, from a stable acetylamido/hydroxido complex formed by reaction of cisplatin with peroxyacetimidic acid (PAIA). NMR spectroscopy and X-ray crystallography confirm the identity of the resulting complexes, and highlight subtle differences in the structure and stability of acetylamido complexes compared to the equivalent acetato complexes.

Haemolymph from Mytilus galloprovincialis: Response to copper and temperature challenges studied by (1)H-NMR metabonomics.

Numerous studies on molluscs have been carried out to clarify the physiological roles of haemolymph serum proteins and haemocytes. However, little is known about the presence and functional role of the serum metabolites. In this study, Nuclear Magnetic Resonance (NMR) was used to assess whether changes of the metabolic profile of Mytilus galloprovincialis haemolymph may reflect alterations of the physiological status of the organisms due to environmental stressors, namely copper and temperature.