Gold(I) metallocyclophosphazenes with antibacterial potency and antitumor efficacy. Synergistic antibacterial action of a heterometallic gold and silver-cyclophosphazene.

One of the most important uses of phosphazenes today involves its biomedical applications. They can also be employed as scaffolds for the design and construction of a variety of ligands in order to coordinate them to metallic drugs. The coordination chemistry of the (amino)cyclotriphosphazene ligand, [N3P3(NHCy)6], towards gold(I) complexes has been studied. Neutral complexes, [N3P3(NHCy)6{AuX}n] (X = Cl or C6F5; n = 1 or 2) (1-4), cationic complexes, [N3P3(NHCy)6{Au(PR3)}n](NO3)n (PR3 = PPh3, PPh2Me, TPA; n = 1, 2 or 3) (6-12) [TPA = 1,3,5-triaza-7-phosphaadamantane] and a heterometallic compound [N3P3(NHCy)6{Au(PPh3)}2{Ag(PPh3)}](NO3)3 (13) have been obtained and characterized by various methods including single-crystal X-ray diffraction for 7, which confirms the coordination of gold atoms to the nitrogens of the phosphazene ring. Compounds 1, 4, 6-13 were screened for in vitro cytotoxic activity against two tumor human cell lines, MCF7 (breast adenocarcinoma) and HepG2 (hepatocellular carcinoma), and for antimicrobial activity against five bacterial species including Gram-positive, Gram-negative, and Mycobacteria. Both the median inhibitory concentration (IC50) and minimum inhibitory concentration (MIC) values are among the lowest found for any gold or silver derivatives against the cell lines and particularly against the Gram-positive (S. aureus) strain and the mycobacteria used in this work. Structure-activity relationships are discussed in order to determine the influence of ancillary ligands and the number and type of metal atoms (silver or gold). Compounds 4 and 8 showed not only maximal potency on human cells but also some tumour selectivity. Remarkably, compound 13, with both gold and silver atoms, showed outstanding activity against both Gram-positive and Gram-negative strains (nanomolar range), thus having a cooperative effect between gold and silver, with MIC values which are similar or lower than those of gentamicine, ciprofloxacin and rifampicine. The broad spectrum antimicrobial efficacy of all these metallophosphazenes and particularly of heterometallic compound 13 could be very useful to obtain materials for surfaces with antimicrobial properties that are increasingly in demand.

Cyclotriphosphazenes as Scaffolds for the Synthesis of Metallomesogens.

(Amino)cyclotriphosphazenes have been used as new scaffolds for the synthesis of silver(I) metallomesogens. Two cyclotriphosphazenes, [N3P3(NHCy)6] (phos-1) and nongem-trans-[N3P3(NHCy)3(NMe2)3] (phos-2), were reacted with the silver complex having a pro-mesogenic ligand, [Ag(OTf)L] (L = CNC6H4{OC(O)C6H2(3,4,5-(OC10H21)3)}-4; OTf = OSO2CF3), in different molar ratios, 1:1, 1:2, or 1:3, to give two series of cationic metallophosphazenes, [N3P3(NHCy)6{AgL}n](TfO)n (phos-1.n) and nongem-trans-[N3P3(NHCy)3(NMe2)3{AgL}n](TfO)n (phos-2.n) with n = 1, 2, or 3. The chemical structure of these compounds, deduced from spectroscopic techniques, was in accordance with coordination of the silver fragments "AgL" to nitrogen atoms of the phosphazene ring, whereby their number n depends on the molar ratio used. Despite the presence of the bulky substituents on the core N atoms, cyclotriphosphazenes coordinated to three "AgL" units exhibited mesomorphism at room temperature. The mesophase was characterized as columnar hexagonal according to the optical microscopy and X-ray diffraction studies. A model based on an intermolecular association in pairs of the metallocyclotriphosphazenes having three AgL units has been proposed in order to explain the mesomorphic columnar arrangement in these materials. Starting silver complex, [Ag(OTf)L], also exhibited a columnar hexagonal mesophase at room temperature.

(Amino)cyclophosphazenes as Multisite Ligands for the Synthesis of Antitumoral and Antibacterial Silver(I) Complexes.

The reactivity of the multisite (amino)cyclotriphosphazene ligands, [N3P3(NHCy)6] and [N3P3(NHCy)3(NMe2)3], has been explored in order to obtain silver(I) metallophosphazene complexes. Two series of cationic silver(I) metallophosphazenes were obtained and characterized: [N3P3(NHCy)6{AgL}n](TfO)n [n = 2, L = PPh3 (2), PPh2Me (4); n = 3, L = PPh3 (3), PPh2Me (5), TPA (TPA = 1,3,5-triaza-7-phosphaadamantane, 6)] and nongem-trans-[N3P3(NHCy)3(NMe2)3{AgL}n](TfO)n [n = 2, L = PPh3 (7), PPh2Me (9); n = 3, L = PPh3 (8), PPh2Me (10)]. 5, 7, and 9 have also been characterized by single-crystal X-ray diffraction, thereby allowing key bonding information to be obtained. Compounds 2-6, 9, and 10 were screened for in vitro cytotoxic activity against two tumor human cell lines, MCF7 (breast adenocarcinoma) and HepG2 (hepatocellular carcinoma), and for antimicrobial activity against five bacterial species including Gram-positive, Gram-negative, and Mycobacteria strains. Both the IC50 and MIC values revealed excellent biological activity for these metal complexes, compared with their precursors and cisplatin and also AgNO3 and silver sulfadiazine, respectively. Both IC50 and MIC values are among the lowest values found for any silver derivatives against the cell lines and bacterial strains used in this work. The structure-activity relationships were clear. The most cytotoxic and antimicrobial derivatives were those with the triphenylphosphane and [N3P3(NHCy)6] ligands. A significant improvement in the activity was also observed upon a rise in the number of silver atoms linked to the phosphazene ring.

Úlcera rectal solitaria en paciente con prolapso rectal / Solitary rectal ulcer in a patient with rectal prolapse

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Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents.

A series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent iminophosphorane ligand derived from 8-aminoquinoline [Ph3P=N-C9H6N] (1), have been synthesized and structurally characterized. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [M{κ3-C,N,N-C6H4(PPh2=N-8-C9H6N}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh 3 fragment. Iminophosphorane 1 and the new metallic complexes are luminescent in DMSO or DMSO:H2O (1:1 mixture) solutions at RT. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A-549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin.

New liquid crystalline materials based on two generations of dendronised cyclophosphazenes.

A divergent approach was used for the synthesis of dendritic structures based on a cyclotriphosphazene core with 12 or 24 hydroxyl groups, by starting from [N(3)P(3)(OC(6)H(4)OH-4)(6)] and using an acetal-protected 2,2-di(hydroxymethyl)propionic anhydride as the acylating agent. Hydroxyl groups in these first- and second-generation dendrimers, G1-(OH)(12) or G2-(OH)(24), were then condensed in turn with mono- or polycatenar pro-mesogenic acids to study their ability to promote self-assembly into liquid crystalline structures. Reactions were monitored by using (31)P{(1)H} and (1)H NMR spectroscopy and the chemical structure of the resulting materials was confirmed by using different spectroscopic techniques and mass spectrometry (MALDI-TOF MS). The results were in accordance with monodisperse, fully functionalised cyclotriphosphazene dendrimers. Thermal and liquid crystalline properties were studied by using optical microscopy, differential scanning calorimetry and X-ray diffraction. The dendrimer with 12 4-pentylbiphenyl mesogenic units gives rise to columnar rectangular organisation, whereas the one with 24 pentylbiphenyl units does not exhibit mesomorphic behaviour. In the case of materials that contain polycatenar pro-mesogenic units with two aromatic rings (A4 vs. A5), the incorporation of a short flexible spacer connected to the periphery of the dendron (acid A5) was needed to achieve mesomorphic organisation. In this case, both dendrimer generations G1 A5 and G2 A5 exhibit a hexagonal columnar mesophase.

Luminescent di- and polynuclear organometallic gold(I)-metal (Au2, {Au2Ag}n and {Au2Cu}n) compounds containing bidentate phosphanes as active antimicrobial agents.

The reaction of new dinuclear gold(I) organometallic complexes containing mesityl ligands and bridging bidentate phosphanes [Au(2)(mes)(2)(µ-LL)] (LL=dppe: 1,2-bis(diphenylphosphano)ethane 1a, and water-soluble dppy: 1,2-bis(di-3-pyridylphosphano)ethane 1b) with Ag(+) and Cu(+) lead to the formation of a family of heterometallic clusters with mesityl bridging ligands of the general formula [Au(2)M(µ-mes)(2) (µ-LL)][A] (M=Ag, A=ClO(4)(-), LL=dppe 2a, dppy 2b; M=Ag, A=SO(3)CF(3)(-), LL=dppe 3a, dppy 3b; M=Cu, A=PF(6)(-), LL=dppe 4a, dppy 4b). The new compounds were characterized by different spectroscopic techniques and mass spectrometry The crystal structures of [Au(2)(mes)(2)(µ-dppy)] (1b) and [Au(2)Ag(µ-mes)(2)(µ-dppe)][SO(3)CF(3)] (3a) were determined by a single-crystal X-ray diffraction study. 3a in solid state is not a cyclic trinuclear Au(2)Ag derivative but it gives an open polymeric structure instead, with the {Au(2)(µ-dppe)} fragments "linked" by {Ag(µ-mes)(2)} units. The very short distances of 2.7559(6) Š(Au-Ag) and 2.9229(8) Š(Au-Au) are indicative of gold-silver (metallophilic) and aurophilic interactions. A systematic study of their luminescence properties revealed that all compounds are brightly luminescent in solid state, at room temperature (RT) and at 77 K, or in frozen DMSO solutions with lifetimes in the microsecond range and probably due to the self-aggregation of [Au(2)M(µ-mes)(2)(µ-LL)](+) units (M=Ag or Cu; LL=dppe or dppy) into an extended chain structure, through Au-Au and/or Au-M metallophilic interactions, as that observed for 3a. In solid state the heterometallic Au(2)M complexes with dppe (2a-4a) show a shift of emission maxima (from ca. 430 to the range of 520-540 nm) as compared to the parent dinuclear organometallic product 1a while the complexes with dppy (2b-4b) display a more moderate shift (505 for 1b to a max of 563 nm for 4b). More importantly, compound [Au(2)Ag(µ-mes)(2)(µ-dppy)]ClO(4) (2b) resulted luminescent in diluted DMSO solution at room temperature. Previously reported compound [Au(2)Cl(2)(µ-LL)] (LL dppy 5b) was also studied for comparative purposes. The antimicrobial activity of 1-5 and Ag[A] (A=ClO(4)(-), SO(3)CF(3)(-)) against gram-positive and gram-negative bacteria and yeast was evaluated. Most tested compounds displayed moderate to high antibacterial activity while heteronuclear Au(2)M derivatives with dppe (2a-4a) were the more active (minimum inhibitory concentration 10 to 1 µg mL(-1)). Compounds containing silver were ten times more active to gram-negative bacteria than the parent dinuclear compound 1a or silver salts. Au(2)Ag compounds with dppy (2b, 3b) were also potent against fungi.

Metallophosphazene precursor routes to the solid-state deposition of metallic and dielectric microstructures and nanostructures on Si and SiO2.

We present a method for the preparation and deposition of metallic microstructures and nanostructures deposited on silicon and silica surfaces by pyrolysis in air at 800 degrees C of the corresponding metallophosphazene (cyclic or polymer). Atomic force microscopy studies reveal that the morphology is dependent on the polymeric or oligomeric nature of the phosphazene precursor, on the preparation method used, and on the silicon substrate surface (crystalline or amorphous) and its prior inductively couple plasma etching treatment. Microscale and nanoscale structures and high-surface-area thin films of gold, palladium, silver, and tin were successfully deposited from their respective newly synthesized precursors. The characteristic morphology of the deposited nanostructures resulted in varied roughness and increased surface area and was observed to be dependent on the precursor and the metal center. In contrast to island formation from noble metal precursors, we also report a coral of SnP(2)O(7) growth on Si and SiO(2) surfaces from the respective Sn polymer precursor, leaving a self-affine fractal structure with a well-defined roughness exponent that appears to be independent (within experimental error) of the average size of the islands. The nature of the precursor will be shown to influence the degree of surface features, and the mechanism of their formation is presented. The method reported here constitutes a new route to the deposition of single-crystal metallic, oxidic, and phosphate nanostructures and thin films on technologically relevant substrates.

Metallocyclo- and polyphosphazenes containing gold or silver: thermolytic transformation into nanostructured materials.

A cyclotriphosphazene bearing two 4-oxypyridine groups on the same phosphorus atom, gem-[N(3)P(3)(O(2)C(12)H(8))(2)(OC(5)H(4)N-4)(2)] (I), and its analogous polymer [{NP(O(2)C(12)H(8))}(0.7){NP(OC(5)H(4)N-4)(2)}(0.3)](n) (II), have been used to prepare gold or silver, cyclic and polymeric, metallophosphazenes. The following complexes, gem-[N(3)P(3)(O(2)C(12)H(8))(2)(OC(5)H(4)N-4{ML})(2)] (ML=Au(C(6)F(5)) (1) or Au(C(6)F(5))(3) (2)), [N(3)P(3)(O(2)C(12)H(8))(2)(OC(5)H(4)N-4{AuPPh(3)})(2)][NO(3)](2) (3), and [N(3)P(3)(O(2)C(12)H(8))(2)(OC(5)H(4)N-4{AgPPh(2)R})(2)][SO(3)CF(3)](2) (R=Ph (4) or Me (5)) have been obtained. Complexes 1 and 4 are excellent models for the preparation of the analogous polymers [{NP(O(2)C(12)H(8))}(0.7){NP(OC(5)H(4)N-4{ML})(2)}(0.3)](n) (ML=Au(C(6)F(5)) (P1), Ag(OSO(2)CF(3))PPh(3) (P2)). All complexes have been characterized by elemental analysis, various spectroscopic methods, and mass spectrometry. The polymers were further investigated by thermochemical methods (thermogravimetric analysis) and differential scanning calorimetry. For compounds 1-5 and for the starting phosphazene I, a mixture of different stereoisomers may be expected. The stereochemistry in solution has been studied by variable-temperature NMR spectroscopy studies, which provided evidence for interconversion processes that involve changes in the chirality of a 2,2'-dioxybiphenyl group. A single-crystal X-ray analysis of the gold complex 2 confirmed not only the proposed structure, but also S,S and R,R configurations at the two biphenoxy-substituted phosphorus centers, in contrast to those observed for the precursor I. Pyrolysis of these new metallophosphazenes was also studied. Notably, pyrolysis of the gold derivatives gave macroporous metallic gold sponges without the requirement of either an external reducing agent or a porous support. These materials were all characterized by XRD, TEM, SEM, and energy-dispersive X-ray spectroscopy.

Columnar mesomorphic organizations in cyclotriphosphazenes.

A synthetic strategy has been developed to prepare cyclotriphosphazenes that bear polycatenar aromatic esters as promesogenic units linked to phosphorus atoms. The microsegregation of the rigid and flexible parts of the system and the space-filling properties are the driving forces that determine the kind of mesomorphism exhibited by the organocyclotriphosphazenes. Mesogenic units that contain only one terminal alkyl chain give rise to calamitic mesomorphism, since the molecules are arranged to give a cylindrical superstructure with the aromatic promesogenic cores elongated in a manner approximately perpendicular to the cyclotriphosphazene ring. On the other hand, mesogenic units that contain three long terminal chains exhibit columnar mesophases. In this case, a discotic structure consisting of promesogenic cores arranged approximately parallel to the cyclotriphosphazene ring can explain the columnar organization. The X-ray diffraction patterns corresponding to the Col(h) mesophase of the cyclotriphosphazene with dodecyloxy chains (8) indicate the presence of helical ordering, which was confirmed for a homologous compound bearing stereogenic centers on two of the terminal chains (11). All of the synthesized phosphazenes show a high thermal stability.

A family of alkynylgold(III) complexes [AuI(mu-{CH2}2PPh2)2Au(III)(C triple bond CR)2] (R = Ph, tBu, Me3Si): facile and reversible comproportionation of gold(I)/gold(III) to digold(II).

The symmetric digold(II)dichloride bis(ylide) complex [Au2Cl2(mu-{CH2}2PPh2)2] reacts with acetylides to form the asymmetric heterovalent gold(I)/gold(III) complexes [AuI(mu-{CH2}2PPh2)2AuIII(CCR)2] [R = Ph, tBu, and SiMe3], the phenyl analogue of which was characterized by X-ray crystallography. These compounds represent the first examples of gold(III) complexes containing two acetylide ligands. [AuI(mu-{CH2}2PPh2)2AuIII(CCPh)2] undergoes a reversible comproportionation reaction upon treatment with [Ag(ClO4)tht] to give the symmetric digold(II) cationic complex [Au2(tht)2(mu-{CH2}2PPh2)2](ClO4)2. If this complex is treated with phenylacetylene in the presence of base, the heterovalent gold(I)/gold(III) complex is re-formed. This reversible interconversion between binuclear gold(I)/gold(III) and digold(II) bis(ylide) complexes is unprecedented.

Synthesis and structure of new carborane-substituted cyclotriphosphazenes.

The reactions of [N(3)P(3)Cl(6)] with one, two, or three equivalents of the difunctional 1,2-closo-carborane C(2)B(10)H(10)[CH(2)OH](2) and K(2)CO(3) in acetone have been investigated. These reactions led to the new spiro-closo-carboranylphosphazenes gem-[N(3)P(3)Cl(6-2n)[(OCH(2))(2)C(2)B(10)H(10)](n)] (n=1 (1), 2 (2)) and the first fully carborane-substituted phosphazene gem-[N(3)P(3)[(OCH(2))(2)C(2)B(10)H(10)](3)] (3). A bridged product, non-gem-[N(3)P(3)Cl(4)[(OCH(2))(2)C(2)B(10)H(10)]] (4), was also detected. The reaction of the well-known spiro derivatives [N(3)P(3)Cl(2)(O(2)C(12)H(8))(2)] and [N(3)P(3)Cl(4)(O(2)C(12)H(8))] with the same carborane-diol and K(2)CO(3) in acetone gave the new compounds gem-[N(3)P(3)(O(2)C(12)H(8))(3-n)[(OCH(2))(2)C(2)B(10)H(10)](n)] (n=1 (5) or 2 (6), respectively), without signs of intra- or intermolecularly bridged species. Upon treatment with NEt(3) in acetone, compound 5 was converted into the corresponding nido-carboranylphosphazene. However, the reaction of gem-[N(3)P(3)(O(2)C(12)H(8))(2)[(OCH(2))(2)C(2)B(10)H(10)]] (5) with NEt(3) in ethanol instead of acetone proceeded in a different manner to give the new compound (NHEt(3))(2)[N(3)P(3)(O(2)C(12)H(8))(2)(O)[OCH(2)C(2)B(9)H(10)CH(2)OCH(2)CH(3)]] (7). For compounds with two 2,2'-dioxybiphenyl units, gem-[N(3)P(3)(O(2)C(12)H(8))(2)[(OCH(2))(2)C(2)B(10)H(10)]] (5), (NHEt(3))[N(3)P(3)(O(2)C(12)H(8))(2)[(OCH(2))(2)C(2)B(9)H(10)]] (8), and (NHEt(3))(2)[N(3)P(3)(O(2)C(12)H(8))(2)(O)[OCH(2)C(2)B(9)H(10)CH(2)OCH(2)CH(3)]] (7), a mixture of different stereoisomers may be expected. However, for 5 and 7 only the meso compounds seem to be formed, with the same (R,S)-configuration as in the precursor [N(3)P(3)Cl(2)(O(2)C(12)H(8))(2)]. The reaction of 5 to give 8 seems to proceed with a change of configuration at one phosphorus center, giving a racemic mixture. The crystal structures of the nido-carboranylphosphazenes 7 and 8 have been confirmed by X-ray diffraction methods.