A discrete Adomian decomposition method for the discrete nonlinear Schrödinger equation

In this work we want to describe a discrete version of the well-known Adomian decomposition method (ADM) applied to nonlinear Schrödinger equations. The ADM was introduced by Adomian in the early 1980s to solve nonlinear ordinary and partial differential equation. This method is an alternative to finite difference and finite element methods; it avoids linearization and yields an efficient numerical solution with high accuracy

A discrete Adomian decomposition method for discrete nonlinear Schrödinger equations

We present a new discrete Adomian decomposition method to approximate the theoretical solution of discrete nonlinear Schrödinger equations. The method is examined for plane waves and for single soliton waves in case of continuous, semi-discrete and fully discrete Schrödinger equations. Several illustrative examples and Mathematica program codes are presented

Design of photoactivatable metallodrugs : selective and rapid light-induced ligand dissociation from half-sandwich [Ru([9]aneS3)(N–N′)(py)]2+ complexes

The synthesis of the inert Ru(II) half-sandwich coordination compounds, [Ru([9]aneS3)(bpy)(py)][PF6]2 (1, [9]aneS3 = 1,4,7-trithiacyclononane, bpy = 2,2′-bipyridine, py = pyridine), [Ru([9]aneS3)(en)(py)][PF6]2 (2, en = 1,2-diaminoethane), and [Ru([9]aneN3)(en)(dmso-S)][PF6]2 (3, [9]aneN3 = 1,4,7-triazacyclononane), is reported along with the X-ray crystal structure of 1. We investigated whether these complexes have photochemical properties which might make them suitable for use as pro-drugs in photochemotherapy. Complexes 1 and 2 underwent rapid (minutes) aquation with dissociation of the pyridine ligand in aqueous solution when irradiated with blue light (λ = 420 or 467 nm). The photodecomposition of 3 was much slower. All complexes readily formed adducts with 9-ethylguanine (9-EtG) when this model nucleobase was present in the photolysis solution. Similarly, complex 1 formed adducts with the tripeptide glutathione (GSH), but only when photoactivated. HPLC and MS studies of 1 showed that irradiation promoted rapid formation of 1:1 (major) and 1:2 (minor) adducts of the oligonucleotide d(ATACATGCTACATA) with the fragment {Ru([9]aneS3)(bpy)}2+. Density functional theory (DFT) calculations and time-dependent DFT reproduced the major features of the absorption spectra and suggested that the lowest-lying triplet state with 3MLCT character, which is readily accessible via intersystem crossing, might be responsible for the observed dissociative behavior of the excited states. These complexes are promising for further study as potential photochemotherapeutic agents

Synthesis of Pt(II) and Ru(II) complexes with biological-interest ligands

The synthesis, characterization and biological properties of novel platinum(II) and ruthenium(II) complexes with dicarboxylate ligands as potential antitumor and antimetastatic agents, are described in this thesis. The platinum complexes were synthesized via solid phase approach, which is a new and very promising technique. According to this method, two amino acids are consecutively condensed to a resin, which is followed by the attachment of the platinum-chelating moiety. Before the cleavage of the resin, the platination takes place. Alternatively, the platination of the linker takes place in advance, and then this conjugate is condensed to the solid fixed dipeptide. The final step in both routes is the cleavage of the solid support (resin) giving the peptide-platinum compound. Two novel compounds were isolated, B614 and B617, which both contain the glycine-glycine dipeptide. In compound Β614, platinum is bound to the peptide by the two carboxylic groups of the linker while two ammonia molecules occupy the other two sites of the platinum coordination sphere. Contrarily, in compound Β617, platinum is bound to a diamine moiety while the chelating ligand 1,1-cyclobutane dicarboxylate (cbdc) occupies the other two sites of the platinum coordination sphere. The characterization of the starting materials, the intermediates and the final compounds has been carried out by means of NMR spectroscopy (1H, 195Pt, COSY) and mass spectroscopy (LCMS). The ruthenium(II) complexes were synthesized following the traditional methods (synthesis in solution) since very little is know about the reactivity of ruthenium towards dicarboxylates. The dicarboxylates which were used were: oxalate (ox), malonate (mal), 1,1-cyclobutane dicarboxylate (cbdc), and succinate (suc). The products obtained were 1) mononuclear (the ligand acts as chelate): K[fac- RuCl(dmso-S)3(η2-ox-O,O/)] (B71), [fac-RuCl(dmso-S)3(η2-ox-O,O/)] (B73), K[fac-RuCl(dmso-S)3(η2-mal- O,O/)]·2H2O (B81), fac-Ru(dmso-S)3(dmso-O)(η2-mal-O,O/) (Β82), K[fac-RuCl(dmso-S)3(η2-cbdc-O,O/)]·2H2O (B91), 2) dinuclear (the ligand acts as bridge): {fac-Ru(dmso-S)3(H2O)(μ-mal-O,O/)}2 (Β83), {fac-Ru(dmso- S)3(H2O)(μ-cbdc-O,O/)}2 (Β92), {fac-Ru(dmso-S)3(NH3)(μ-cbdc-O,O/)}2 (Β93), {fac-Ru(dmso-S)3(H2O)(μ-suc- O,O/)}2 (Β101), 3) dinuclear (the ligand acts as bis-bidentate): [{fac-Ru(dmso-S)3(Cl)}2(η4,μ-ox)] (B72), [{fac- Ru(dmso-S)3(dmso-O)}2(η4,μ-ox)](CF3SO3)2 (B74) and 4) tetranuclear (the ligand acts both as chelate and bridge): {fac-Ru(dmso-S)3(η3,μ-ox)}4 (Β75). All complexes were fully characterized by elemental analysis and variety of spectroscopic methods such as 1D and 2D NMR (1H, 13C, COSY, HMQC), IR, UV-Vis. The molecular structures of the complexes Β72, Β74, Β75, Β81, Β82, Β83, Β92, Β93 και Β101 were determined by X-Ray crystallography. The chemical behavior in aqueous solution of all Ru-dmso-dicarboxylate complexes was extensively studied, and some in vitro biological experiments were performed in order to evaluate their potential antitumor activity.Στη παρούσα διατριβή περιγράφεται η σύνθεση, ο χαρακτηρισμός και διάφορες μελέτες βιολογικού ενδιαφέροντος νέων συμπλόκων του λευκοχρύσου(ΙΙ) και του ρουθηνίου(ΙΙ) που περιέχουν δικαρβοξυλικούς υποκαταστάτες, ως ενδεχόμενα αντικαρκινικά και αντιμεταστατικά μέσα. Για τη σύνθεση των συμπλόκων λευκοχρύσου χρησιμοποιήθηκε μια καινούργια και πολύ ελπιδοφόρα τεχνική, η σύνθεση μέσω στερεάς φάσης. Σύμφωνα με αυτή δύο αμινοξέα προσκολλούνται διαδοχικά σε μια ρητίνη, στη συνέχεια προσκολλάται ένας «σύνδεσμος» και μετά γίνεται η σύμπλεξη του λευκοχρύσου. Εναλλακτικά, πρώτα γίνεται η σύνθεση του συμπλόκου «σύνδεσμος»-Pt και στη συνέχεια αυτό προσκολλάται στο διπεπτίδιο. Το τελικό στάδιο και στις δύο πορείες είναι η αποκοπή της ρητίνης και η παραλαβή του ελεύθερου συμπλόκου. Απομονώθηκαν δύο νέα σύμπλοκα, το Β614 και Β617, στα οποία το διπεπτίδιο ήταν το διπεπτίδιο γλυκίνη-γλυκίνη. Στο Β614 το άκρο του «συνδέσμου» ήταν ένα δικαρβοξύλιο στο οποίο ο PtII ήταν δεσμευμένος χηλικά ενώ οι άλλες δύο θέσεις στη σφαίρα σύνταξης του μετάλλου ήταν κατειλημμένες από δύο μόρια ΝΗ3. Στο Β617 το άκρο ήταν ένα τμήμα αιθυλενοδιαμίνης (en) στην οποία ο PtII ήταν και πάλι δεσμευμένος χηλικά ενώ οι άλλες δύο θέσεις ήταν κατειλημμένες από τον δισθενή χηλικό υποκαταστάτη 1,1- κυκλοβούτανο δικαρβοξυλικό ιόν (1,1-cyclobutane dicarboxylate, cbdc). Τα αρχικά αντιδραστήρια, τα ενδιάμεσα προϊόντα και τα τελικά σύμπλοκα χαρακτηρίσθηκαν με φασματοσκοπία NMR (1H, 195Pt) και φασματομετρία μάζας (MS). Τα σύμπλοκα του ρουθηνίου συντέθηκαν με τους παραδοσιακούς τρόπους (σε διάλυμα) καθώς πολύ λίγα είναι γνωστά για την αλληλεπίδραση δικαρβοξυλίων με ιόντα RuΙΙ. Οι δικαρβοξυλικοί υποκαταστάτες που χρησιμοποιήθηκαν ήταν: τα οξαλικά (oxalate, ox), τα μηλονικά (malonate, mal), τα ηλεκτρικά (succinate, suc) και τα 1,1-κυκλοβούτανοδιικά (cbdc) ιόντα. Τα σύμπλοκα που απομονώθηκαν, ανάλογα με τις συνθήκες, ήταν 1) μονομερή (στα οποία ο υποκαταστάτης δρα δισχιδως/χηλικά): K[fac-RuCl(dmso-S)3(η2-ox-O,O/)] (B71), fac-[Ru(dmso-S)3(dmso-O)(η2-ox-O,O/)] (B73), K[fac-RuCl(dmso-S)3(η2-mal-O,O/)]·2H2O (B81), fac-[Ru(dmso-S)3(dmso-O)(η2-mal-O,O/)] (Β82), K[fac- RuCl(dmso-S)3(η2-cbdc-O,O/)]·2H2O (B91), 2) διμερή (στα οποία ο υποκαταστάτης δρα ως γέφυρα, με το κάθε καρβοξύλιο να συμπλέκεται μονοσχιδώς): {fac-Ru(dmso-S)3(H2O)(μ-mal-O,O/)}2 (Β83), {fac-Ru(dmso- S)3(H2O)(μ-cbdc-O,O/)}2 (Β92), {fac-Ru(dmso-S)3(NH3)(μ-cbdc-O,O/)}2 (Β93), {fac-Ru(dmso-S)3(H2O)(μ-suc- O,O/)}2 (Β101), 3) διμερή (στα οποία ο υποκαταστάτης δρα δισ-δισχιδώς): [{fac-Ru(dmso-S)3(Cl)}2(η4,μ-ox)] (B72), [{fac-Ru(dmso-S)3(dmso-O)}2(η4,μ-ox)](CF3SO3)2 (B74) και 4) τετραμερές (στο οποίο ο υποκαταστάτης δρα χηλικά και συγχρόνως γέφυρα μέσω του ενός από τα δύο ελεύθερα άτομα οξυγόνου): {fac-Ru(dmso- S)3(η3,μ-ox)}4 (Β75). Όλα τα σύμπλοκα χαρακτηρίσθηκαν πλήρως με στοιχειακή ανάλυση και διάφορες φασματοσκοπικές μεθόδους όπως NMR (1H, 13C, COSY, HMQC), IR, UV-Vis. Επίσης οι μοριακές δομές των συμπλόκων Β72, Β74, Β75, Β81, Β82, Β83, Β92, Β93 και Β101 προσδιορίσθηκαν με κρυσταλλογραφία ακτίνων-Χ. Μελετήθηκε εκτενώς η χημική συμπεριφορά αυτών των συμπλόκων εντός υδατικών διαλυμάτων και πραγματοποιήθηκαν in vitro βιολογικές δοκιμασίες για να εκτιμηθεί η ενδεχόμενη αντικαρκινική τους δράση

Structural studies on metallobleomycins: The interaction of Pt(II) and Pd(II) with bleomycin

Two of the most successful chemotherapeutic agents used in the treatment of several neoplasias are bleomycin and cisplatin. Both drugs attack the DNA leading to the cancer cells death via different mechanisms. In view of the fact that the combination with each other leads to enhanced activity with less sever side effects, we have undertaken NMR studies on the complexes formed between bleomycin and PtII, PdII, cisplatin and transplatin. Herein we present a brief review of the studies on metallobleomycins which were carried out by our lab and others, as an outline of the results obtained using NMR in combination to circular dichroism spectroscopy. Our data indicate that in most cases and under several conditions studied, both metal ions form similar complexes with BLM, while more than one species are present in the solution. Structural implications and comparisons with other metallobleomycins are being discussed

Original scientific paper

Structural studies on metallobleomycins: The interaction o

Insights into the Protein Ruthenation Mechanism by Antimetastatic Metallodrugs: High-Resolution X-ray Structures of the Adduct Formed between Hen Egg-White Lysozyme and NAMI-A at Various Time Points

The pharmacological profile of medicinally relevant Ru(III) coordination compounds has been ascribed to their interactions with proteins, as several studies have provided evidence that DNA is not the primary target. In this regard, numerous spectroscopic and crystallographic studies have indicated that the Ru(III) ligands play an important role in determining the metal binding site, acting as the recognition element in the early stages of the protein–complex formation. Herein, we present a series of near-atomic-resolution X-ray crystal structures of the adducts formed between the antimetastatic metallodrug imidazolium trans-[tetrachlorido(S-dimethyl sufoxide)(1H-imidazole)ruthenate(III)] (NAMI-A) and hen egg-white lysozyme (HEWL). These structures elucidate a series of binding events starting from the noncovalent interaction of intact NAMI-A ions with HEWL (1.5 h), followed by the stepwise exchange of all Ru ligands except for 1H-imidazole (26 h) to the final “ruthenated” protein comprising one aquated Ru ion coordinated to histidine-15 of HEWL (98 h). Our structural data clearly support a two-step mechanism of protein ruthenation, illustrating the ligand-mediated recognition step of the process

Ruthenium Anticancer Compounds: Challenges and Expectations

Two ruthenium compounds, namely [ImH]trans-[RuCl4(Im)(dmso-S)] (NAMI-A, Im = imidazole) and [IndH] trans-[RuCl4(Ind)2] (KP1019, Ind = indazole) have already completed phase I clinical trials as anticancer agents. They both have properties different from platinum anticancer drugs: for example, NAMI-A is selectively active against metastases of solid tumors. They show that in the field of anticancer metal drugs a new approach, based on targeted therapies, is possible. After a concise history of ruthenium anticancer compounds, this contribution will focus on ruthenium-dmso complexes and, in particular, on NAMI-A. Particular emphasis is given on the challenges that are inherent to this field: how to develop new anticancer ruthenium compounds and how to select new active compounds that manifest their anticancer activity through non-conventional mechanisms

New Cationic and Neutral Ru(II)- and Os(II)-dmso carbonyl Compounds

The preparation and structural characterization of three cationic Ru(II)-dmso carbonyls and of four neutral mono- and dicarbonyl Os(II)-dmso derivatives is reported. The two monocarbonyl species fac-[Ru(CO)(dmso-O)3 (dmso-S)2][PF6]2 (11) and cis,cis,cis-[RuCl(CO)(dmso-O)2(dmso-S)2][PF6] (12) were obtained from the neutral monocarbonyl precursor cis,trans,cis-[RuCl2(CO)(dmso-O)(dmso-S)2] (3) upon stepwise replacement of the chlorides with dmso, that binds in each case through the oxygen atom. The dicarbonyl cationic complex cis,cis,trans-[Ru(CO)2(dmso-O)2(dmso-S)Cl][PF6] (13) was instead obtained upon treatment of the neutral tricarbonyl precursor fac-[RuCl2(CO)3(dmso-O)] (8) with AgPF6 in the presence of DMSO: replacement of a Cl 12 with a dmso-O impliedalso the substitution of one CO ligand by another dmso (that binds through S trans to Cl). The Os(II) carbonyls trans,trans,trans-[OsCl2(CO)(dmso-O)(dmso-S)2] (17), trans,cis,cis-[OsCl2(CO)2(dmso-O)2] (18), cis,mer-[OsCl2(CO)(dmso-S)3] (19), and cis,trans,cis-[OsCl2(CO)(dmso-O)(dmso-S)2] (20) were obtained by treatment of the Os(II)-dmso precursors trans-[OsCl2(dmso-S)4] (14) and cis,fac-[OsCl2(dmso-O)(dmso-S)3] (15) with CO. Each one of them is structurally similar to an already known Ru(II) analog, even though - in agreement with the expected greater inertness of Os(II) - more forcing reaction conditions were required for their preparation. Interestingly, compound 20 could not be isolated in pure form, but only as a 1:1 cocrystallized mixture with its precursor 15. The dmso ligand is always bound through the oxygen atom when trans to CO. We are con \ufb01 dent that the new Ru(II)- and Os(II)-dmso carbonyl species described here represent a contribution to expand the pool of complexes bearing some easily replaceable dmso ligands to be used as well-behaved precursors in inorganic synthesis