Carmen R. Maldonado

Nanoscaled Zinc Pyrazolate Metal–Organic Frameworks as Drug-Delivery Systems

This work describes synthesis at the nanoscale of the isoreticular metal-organic framework (MOF) series ZnBDP_X, based on the assembly of Zn(II) metal ions and the functionalized organic spacers 1,4-bis(1H-pyrazol-4-yl)-2-X-benzene (H2BDP_X; X = H, NO2, NH2, OH). The colloidal stability of these systems was evaluated under different relevant intravenous and oral-simulated physiological conditions, showing that ZnBDP_OH nanoparticles exhibit good structural and colloidal stability probably because of the formation of a protein corona on their surface that prevents their aggregation. Furthermore, two antitumor drugs (mitroxantrone and [Ru(p-cymene)Cl2(pta)] (RAPTA-C) where pta = 1,3,5-triaza-7-phospaadamantane) were encapsulated within the pores of the ZnBDP_X series in order to investigate the effect of the framework functionalization on the incorporation/delivery of bioactive molecules. Thus, the loading capacity of both drugs within the ZnBDP_X series seems to directly depend on the surface area of the solids. Moreover, ligand functionalization significantly affects both the delivery kinetics and the total amount of released drug. In particular, ZnBDP_OH and ZnBDP_NH2 matrixes show a slower rate of delivery and higher percentage of release than ZnBDP_NO2 and ZnBDP_H systems. Additionally, RAPTA-C delivery from ZnBDP_OH is accompanied by a concomitant and progressive matrix degradation due to the higher polarity of the BPD_OH ligand, highlighting the impact of functionalization of the MOF cavities over the kinetics of delivery.

Copper (II) complexes of [1,2,4]triazolo [1,5-a]pyrimidine derivatives as potential anti-parasitic agents.

Anti-proliferative effects are described for newly synthesised copper (II) complexes of two triazolo-pyrimidine derivatives (1,2,4-triazolo-[1,5-a]pyrimidine, tp, and 5,7-dimethyl 1,2,4-triazolo-[1,5-a]pyrimidine, dmtp) against to Trypanosoma cruzi and Leishmania (Viannia) peruviana. Of the compounds assayed, those that presented the ligand tp and auxiliary ligand 1,10-phenanthroline (C24b, C49) were most highly active against to T. cruzi with IC(50) within the range of the reference drug benznidazole. These compounds, together with C35 were the most effective against L. (V.) peruviana with an IC(50) greater than that presented by reference drugs (Pentostam and Glucantim). These compounds were not toxic to the host cell. IC(25) diminished the infection capacity and severely reduced the multiplication of intracellular forms of T. cruzi, and L. (V.) peruviana. In the case of T. Cruzi, the transformation to trypomastigote was seriously depressed. Copper (II) complexes C24b, C49 and C35, acted on the energy metabolism of the parasites at the level of the NAD(+)/NADH balance and at the level of the organelle membranes, causing degradation and cell death.

In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis

Studies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death.

RAPTA-C incorporation and controlled delivery from MIL-100(Fe) nanoparticles

[Fe3F(H2O)2O(btc)2]·nH2O (H3btc: benzene-1,3,5-tricarboxylic acid) (MIL-100(Fe)) in the form of nanoparticles with average size of 135 ± 70 nm can be used for the adsorption and controlled delivery of metallodrug [Ru(p-cymene)Cl2(pta)] (RAPTA-C) in simulated body fluid (SBF). The results show that the RAPTA-C delivery process takes place in two steps exhibiting half-life times of 1.9 and 30 h. We also found a positive effect of bovine serum albumine (BSA) in speeding up the RAPTA-C delivery rate, which agrees with the suitability of MIL-100(Fe) as a drug delivery system (DDS) for the controlled release of RAPTA-C.

Inorganic mesoporous silicas as vehicles of two novel anthracene-based ruthenium metalloarenes.

Two novel anthracene-based half-sandwich organometallic Ru(II) compounds, namely, [Ru(p-cymene)(L1)Cl2] (1) and [Ru(p-cymene)(L2)Cl2] (2) (L1=1-(anthracen-9-yl)-N-(pyridin-3-ylmethyl)methanamine; L2=1-(anthracen-9-yl)-N-(pyridin-4-ylmethyl)methanamine) have been synthesized and characterized. We demonstrate that the fluorescence properties of these complexes are highly affected by the linking position of the anthracene unit, as only 2 shows fluorescence emission in the blue region. Regarding their biological activity, both ruthenium metallodrugs show interaction with different biological targets such as S-donor amino acids (cysteine) and proteases (cysteine cathepsin B). Moreover, 1 and 2 show in vitro cytotoxicity against HL-60 cancer cell line (IC50=84.5 and 87.0μM for 1 and 2, respectively), with cell death occurring via apoptosis. Further studies have shown that diffusion into cells is the main mechanism of metallodrug uptake. Finally, as a proof of concept, these ruthenium complexes have been successfully encapsulated into MCM-41 and SBA-15 mesoporous silicas using two different incorporation strategies (impregnation and grinding).

Silver(I)‐Mediated Base Pairs in DNA Sequences Containing 7‐Deazaguanine/Cytosine: towards DNA with Entirely Metallated Watson–Crick Base Pairs

DNA sequences comprising noncanonical 7-deazaguanine (7C G) and canonical cytosine (C) are capable of forming Watson-Crick base pairs via hydrogen bonds as well as silver(I)-mediated base pairs by coordination to central silver(I) ions. Duplexes I and II containing 7C G and C have been synthesized and characterized. The incorporation of silver(I) ions into these duplexes has been studied by means of temperature-dependent UV spectroscopy, circular dichroism, and DFT calculations. The results suggest the formation of DNA molecules comprising contiguous metallated 7C G-AgI -C Watson-Crick base pairs that preserve the original B-type conformation. Furthermore, additional studies performed on duplex III indicated that, in the presence of AgI ions, 7C G-C and 7C A-T Watson-Crick base pairs (7C A, 7-deazadenine; T, thymine) can be converted to metallated 7C G-AgI -C and 7C A-AgI -T base pairs inside the same DNA molecule whilst maintaining its initial double helix conformation. These findings are very important for the development of customized silver-DNA nanostructures based on a Watson-Crick complementarity pattern.

Aluminum Doped MCM-41 Nanoparticles as Platforms for the Dual Encapsulation of a CO-Releasing Molecule and Cisplatin

Mesoporous silica Al-MCM-41 nanoparticles have been used, for the first time, as vehicles for the single and dual encapsulation of the cationic CO-releasing molecule (CORM) [Mn(1,4,7-triazacyclononane)(CO)3]+ (ALF472+) and the well-known antineoplastic drug, cis-[PtCl2(NH3)2] (cisplatin). Thus, two new hybrid materials, namely, ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41, have been isolated and fully characterized. The results reveal that the presence of CORM molecules enhances cisplatin loading 3-fold, yielding a cargo of 0.45 mmol g-1 of ALF472+ and 0.12 mmol g-1 of the platinum complex for ALF472-cisplatin@Al-MCM-41. It is worth noting that ALF472@Al-MCM-41 shows a good dispersion in phosphate buffered saline solution, while the dual hybrid material slightly aggregates in this simulated physiological medium (hydrodynamic size: 112 ± 23 and 336 ± 50 nm, respectively). In addition, both hybrid materials (ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41) behave as photoactive CO-releasing materials, delivering 0.25 and 0.11 equiv of CO, respectively, after 24 h and exhibiting a more controlled CO delivery than that of the free CORM. Finally, metal leaching studies have confirmed the good retention capacity of Al-MCM-41 toward the potentially toxic manganese fragments (86% of retention after 72 h) as well as the low release of cisplatin (ca. 7% after 72 h).

A combined experimental and DFT investigation on the structure and CO-releasing properties of mono and binuclear fac-ReI(CO)3 complexes with 5-pyridin-2-ylmethylene-amino uracils

The synthesis, structure and CO-releasing properties of a number of new tricarbonyl rhenium(i) complexes with 5-substituted-6-amino-1,3-dimethyluracils are reported and their structural features discussed on the basis of both spectral and X-ray crystallographic analyses. The 5-substituent library includes -N[double bond, length as m-dash]CH-2py (DAAUPic) and -CH[double bond, length as m-dash]N-N[double bond, length as m-dash]CH-2py (FDUHzPic) as additional metal binding components and chloride, acetonitrile or pyridine acting as ancillary ligands. The compounds have been identified by elemental analysis, NMR, MS and IR spectroscopy. In addition, [ReCl(CO)3(DAAUPic)], [Re(CO)3(FDUHzPic)py]ClO4, [Re(CO)3(FDUHzPic)py]PF6, [Re2Cl2(CO)6(FDUHzPic)] and [Re2Cl(CO)6(FDUHzPicH-1)(H2O)] structures have been solved by X-ray diffraction methods. These studies have clearly shown that the preferred coordination mode to rhenium takes place through the (N1F,N52)-pyridin-2-yl-methyleneamine moiety, the uracil coordinative availability (O4-N51 or N6-N51) being used only to bind the second metal center. The CO-releasing ability of these rhenium compounds has been investigated by the reaction with myoglobin; the corresponding studies have revealed that two of the mononuclear complexes and their related binuclear analogues are able to release CO to a moderate extent. This ability has also been theoretically assessed through a QTAIM analysis. The results, although non-conclusive, may explain somehow possible different preferences in CO releasing power after a comparison between the nature of Re-CO links in mononuclear and binuclear compounds.

5-Methylsulfanyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-one (2-methylthio-8-azaxanthine) monohydrate.

The title compound, C 5 H 5 N 5 OS·H 5 O, crystallizes as the monohydrate. Disorder of the H atoms that participate in the hydrogen bonds implies that two different tautomers are present in the crystal structure, one of them with both acidic H atoms attached to the imidazole ring and the other with one acidic H atom on each ring.