1,721,418 research outputs found
Cisplatin binding to proteins: A structural perspective
No full textThe interactions of clinically established anticancer Pt-based drugs with proteins play crucial roles in Pt cellular uptake and biodistribution, as well as in determining side effects and resistance, thus affecting the overall pharmacological profile of this class of drugs. Here, we summarize a number of recent crystallographic studies of cisplatin/protein adducts that contribute unveiling the molecular basis for cisplatin-protein recognition. Details of each molecular structure are carefully and comparatively described; common trends and regularities occurring in the analyzed adducts are highlighted. Analysis of the structural features of its protein derivatives, integrated with selected results arising from the application of other biophysical methods on strictly related systems, allows an overall elucidation of the protein platination process and offers a more comprehensive understanding of the mode of action of cisplatin and its parent Pt-based drug
Exafs Studies On Copper Transferrin
No full textEXAFS spectra of the dicopper and monocopper complexes of human serum transferrin have been recorded and compared to those of the native iron derivative. The experimental data have been analyzed by comparison with EXAFS data obtained from copper(II) model compounds. Evidence is provided for a more regular metal chromophore in copper transferrin with respect to native iron transferrin. No major intersite differences were observed. The results are discussed in light of the recently reported crystal structures of iron transferrins and copper lactoferrin
Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts
Full text linkOxaliplatin and carboplatin are two platinum(II) drugs in widespread clinical use for the treatment of various types of cancers; yet, structural information on their interactions with proteins is scarce. Here, the X-ray structures of the adducts formed upon reaction of carboplatin and oxaliplatin with bovine pancreatic ribonuclease (RNase A) are reported and compared with results obtained for the structure of the RNase A-cisplatin adduct derived from isomorphous crystals, under the same experimental conditions. Additional details on the binding mode of these metallodrugs toward RNase A are provided by electrospray ionization mass spectrometry (ESI MS) measurements, thus offering insight on the occurring metal-protein interactions. Notably, while carboplatin and cisplatin mainly bind the side chain of Met29, oxaliplatin also binds the side chains of Asp14, of catalytically important His119 and, to a lesser extent, of His105. On the basis of the available data, a likely mechanism for oxaliplatin hydrolysis and binding to the protein is proposed. These results are potentially useful for a better understanding of the biological chemistry, toxicity and side effects of this important class of antitumor agent
Platinum-based Anticancer Drugs: Unveiling Novel Mechanisms of Action of Conventional Metallodrugs for Improved Therapies
No full textAbstract not availabl
NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry
Full text linkNAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(Ind)2]) are two structurally related ruthenium(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemistry scientific community as promising anticancer drug candidates. This has led to a considerable amount of studies on their respective chemico-biological features and to the eventual admission of both to clinical trials. The encouraging pharmacological performances qualified KP1019 mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers, whereas the non-cytotoxic NAMI-A has gained the reputation of being a very effective antimetastatic drug. A critical and strictly comparative analysis of the studies conducted so far on NAMI-A and KP1019 allows us to define the state of the art of these experimental ruthenium drugs in terms of the respective pharmacological profiles and potential clinical applications, and to gain some insight into the inherent molecular mechanisms. Despite their evident structural relatedness, deeply distinct biological and pharmacological profiles do emerge. Overall, these two iconic ruthenium complexes form an exemplary and unique case in the field of medicinal inorganic chemistry
Exafs Studies On the Oxalate Adduct of Iron Transferrin
No full textEXAFS spectra have been collected on the oxalate complex of iron serum transferrin and compared to those of carbonate transferrin. Significant changes have been observed in the amplitude and position of the peaks in the Fourier transforms. The observed behavior is a clear indication for structural changes in the chromophore and in the conformation of the metal environment. The binding mode of the oxalate anion to the iron center is discussed
Iridium(I) Compounds as Prospective Anticancer Agents: Solution Chemistry, Antiproliferative Profiles and Protein Interactions for a Series of Iridium(I) N-Heterocyclic Carbene Complexes
Full text linkAseries of structurally related mono-and bis-NHC–iridium(I) (NHC:N-heterocyclic carbene) complexeshave been investigatedfor their suitability as potential anti-cancer drugs.Their spectral behaviour in aqueous buffersunder physiologic al-like conditions and their cytotoxicityagainstthe cancercell lines MCF-7 and HT-29are reported.Notably,almostall complexes exhibit significant cytotoxic ef-fects towards both cancer cell lines. In general,the cationicbis-carbene complex es show higherstabilityand greater an-ticanceractivity than their neutral mono-carbene analogueswith IC50valuesinthe high nanomolar range.Furthermore,to gain initialmechanistic insight, the interactions of theseiridium(I)–NHC complexes with two model proteins,namelylysozyme and cytochrome c, were exploredbyHR-ESI-MSanalyses. The different protein metalation patternsofthecomplexes can be roughlyclassified into two distinctgroups. Those interactions give us afirst idea about the pos-sible mechanism of action of this class of compounds. Over-all, our findings show that iridium(I)–NHC complexesrepre-sent very interesting candidates forfurther development asnew metal-based anticancer drugs
Reactions of proteins with a few organopalladium compounds of medicinal interest
No full textPd compounds form a promising class of experimental anticancer drug candidates whose mechanism of action is still largely unknown; in particular, a few organopalladium compounds seem very attractive. To gain mechanistic insight into medicinal palladium compounds, we have explored here - through ESI MS analysis - the interactions of four organopalladium agents (1-4) - showing remarkable in vitro antiproliferative properties - with a few representative model proteins, i.e., lysozyme (HEWL), ribonuclease A (RNase), and carbonic anhydrase (hCAI). The tested panel included three Pd allyl compounds with one or two carbene ligands and a palladacyclopentadienyl complex. Notably, the Pd allyl compounds turned out to manifest, on the whole, a modest tendency to react with the above proteins. Only complex 3 produced small amounts of characteristic adducts with hCAI bearing either one or two Pd allyl groups. In contrast, the palladacyclopentadienyl complex 4 manifested a greater and peculiar reactivity with all the above proteins generating invariably protein adducts with a mass increase of +256 Da where a butadienyl group - with no associated Pd - is attached to the proteins. Afterwards, we extended our investigations to the C-terminal dodecapeptide of thioredoxin reductase bearing the -Cys-Sec- reactive motif. In this latter case adducts were formed with all tested Pd compounds; however, complex 4 manifested towards this dodecapeptide a type of reactivity deeply different from that observed with HEWL, RNase A and hCAI. The mechanistic implications of these findings are discussed
Cisplatin encapsulation within a ferritin nanocage: A high-resolution crystallographic study
No full textCisplatin (CDDP) can be encapsulated within the central cavity of reconstituted (apo)ferritin, (A)Ft, to form a drug-loaded protein of potential great interest for targeted cancer treatments. In this study, the interactions occurring between cisplatin and native horse spleen Ft in CDDP-encapsulated AFt are investigated by high-resolution X-ray crystallography. A protein bound Pt center is unambiguously identified in AFt subunits by comparative analysis of difference Fourier electron density maps and of anomalous dispersion data. Indeed, a [Pt(NH3)2H2O](2+) fragment is found coordinated to the His132 residue located on the inner surface of the large AFt spherical cage. Remarkably, Pt binding does not alter the overall physicochemical features (shape, volume, polarity/hydrophobicity and electrostatic potential) of the outer surface of the AFt nanocage. CDDP-encapsulated AFt appears to be an ideal nanocarrier for CDDP delivery to target sites, as it possesses high biocompatibility and can be internalized by receptor mediated endocytosis, thus carrying the drug to tumor tissue with higher selectivity than free CDD
Oxaliplatin vs. cisplatin: Competition experiments on their binding to lysozyme
No full textThe model protein hen egg white lysozyme was challenged
with Oxaliplatin and Cisplatin. ESI mass spectrometry,
surface plasmon resonance and thermal shift analyses
demonstrate the formation of a bis-platinum adduct, though
in very small amounts. Crystals of the bis-platinum adduct
were obtained using two different preparations and the X-ray
structures solved at 1.85 Ǻ and 1.95 Ǻ resolution. Overall, the
obtained data point out that, under the analyzed conditions,
the two Pt drugs have similar affinities for the protein, but
bind on its surface at two non-overlapping sites. In other
words, these two drugs manifest a significantly different
reactivity with this model protein and do not compete for the
same protein binding sites
- …
