Marta S. C. Henriques

Synthesis of New 2-Halo-2-(1H-tetrazol-5-yl)-2H-azirines via a Non-Classical Wittig Reaction

The synthesis and reactivity of tetrazol-5-yl-phosphorus ylides towards N-halosuccinimide/TMSN3 reagent systems was explored, opening the way to new haloazidoalkenes bearing a tetrazol-5-yl substituent. These compounds were obtained as single isomers, except in one case. X-ray crystal structures were determined for three derivatives, establishing that the non-classical Wittig reaction leads to the selective synthesis of haloazidoalkenes with (Z)-configuration. The thermolysis of the haloazidoalkenes afforded new 2-halo-2-(tetrazol-5-yl)-2H-azirines in high yields. Thus, the reported synthetic methodologies gave access to important building blocks in organic synthesis, vinyl tetrazoles and 2-halo-2-(tetrazol-5-yl)-2H-azirine derivatives.

Structure and Photochemistry of a Saccharyl Thiotetrazole

The molecular structure and photochemistry of 5-thiosaccharyl-1-methyltetrazole (TSMT) were studied by means of matrix-isolation FTIR spectroscopy, X-ray crystallography, and theoretical calculations. The calculations predicted two conformers of TSMT that differ in energy by more than 15 kJ mol(-1). The infrared spectrum of TSMT isolated in solid argon was fully assigned on the basis of the spectrum calculated (O3LYP/6-311++G(3df,3pd)) for the most stable conformer. In the crystal, TSMT molecules were found to assume the same conformation as for the isolated molecule, with each molecule forming four hydrogen bonds with three neighboring molecules, leading to a network of TSMT oligomers. Upon UV (λ = 265 nm) irradiation of the matrix-isolated TSMT, two photodegradation pathways were observed, both arising from cleavage of the tetrazolyl ring. Pathway a involves cleavage of the N1-N2 and N3-N4 bonds with extrusion of N2, leading to photostable diazirine and thiocarbodiimide derivatives. The photostability of the photoproduced diazirine under the conditions used precluded its rearrangement to the nitrile imine, as reported for 5-phenyltetrazole by Bégué et al. ( J. Am. Chem. Soc. 2012 , 134 , 5339 ). Pathway b involves cleavage of the C5-N1 and N4-N3 bonds, leading to a thiocyanate and methyl azide, the latter undergoing subsequent fragmentation to give CNH.

Exploring saccharinate-tetrazoles as selective Cu(II) ligands: structure, magnetic properties and cytotoxicity of copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles

The role of copper in the proliferation of cancer cells is under investigation and has been explored in the context of cancer chemotherapy. The evidence that proliferation of cancer cells requires a higher abundance of Cu(II) than their normal counterparts has prompted the development of new copper chelators that can avidly bind copper ions, forming redox active metal complexes that ultimately lead to harmful reactive oxygen species (ROS) in neoplasms. In this context, the mandatory properties of the chelators for medical applications are safety (neglectable cytotoxicity), high binding affinity and selectivity towards Cu(II). We report the synthesis, structure (calculations and single crystal X-ray diffraction), spectroscopic (IR; UV-Vis) and magnetic properties of two novel copper(II) complexes based on 5-(3-aminosaccharyl)-tetrazoles (TS and 2MTS), as well as their in vitro cytotoxicity against the human hepatic carcinoma cell line HepG2. Quite interestingly, we found that the saccharinate-tetrazoles tested exhibit strong binding selectivity to Cu(II), over Fe(II) and Ca(II). Additionally, the corresponding copper complexes have shown a huge increase in the in vitro cytotoxicity against tumoral cells, compared to the corresponding nontoxic ligands. Thus, the new ligands may be viewed as potential precursors of selective cytotoxic agents, acting as non-cytotoxic pro-drugs that can be activated inside neoplastic cells, known to be richer in Cu(II) than the corresponding normal cells.

Crystal structure, matrix-isolation FTIR, and UV-induced conformational isomerization of 3-quinolinecarboxaldehyde.

The crystal structure of 3-quinolinecarboxaldehyde (3QC) has been solved, and the compound has been shown to crystallize in the space group P21/c (monoclinic) with a = 6.306(4), b = 18.551(11), c = 6.999(4) Å, β = 106.111(13)°, and Z = 4. The crystals were found to exhibit pseudomerohedral twinning with a twin law corresponding to a two-fold rotation around the monoclinic (100) reciprocal lattice axis (or [4 0 1] in direct space). Individual molecules adopt the syn conformation in the crystal, with the oxygen atom of the aldehyde substituent directed toward the same side of the ring nitrogen atom. In the gas phase, the compound exists in two nearly isoenergetic conformers (syn and anti), which could be successfully trapped in solid argon at 10 K, and their infrared spectra are registered and interpreted. Upon in situ irradiation of matrix-isolated 3QC with UV light (λ > 315 nm), significant reduction of the population of the less stable anti conformer was observed, while that of the conformational ground state (syn conformer) increased, indicating occurrence of the anti → syn isomerization. Upon irradiation at higher energy (λ > 235 nm), the syn → anti reverse photoreaction was observed. Interpretation of the structural, spectroscopic, and photochemical experimental data received support from quantum chemical theoretical results obtained at both DFT/B3LYP (including TD-DFT investigation of excited states) and MP2 levels, using the 6-311++G(d,p) basis set.

Synthesis, Structure and Cytotoxicity of a Novel Sulphanyl-Bridged Thiadiazolyl-Saccharinate Conjugate. The Relevance of S…N Interaction

Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an S⋅⋅⋅N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.

Highly fluorescent and superparamagnetic nanosystem for biomedical applications

This work reports on highly fluorescent and superparamagnetic bimodal nanoparticles (BNPs) obtained by a simple and efficient method as probes for fluorescence analysis and/or contrast agents for MRI. These promising BNPs with small dimensions (ca. 17 nm) consist of superparamagnetic iron oxide nanoparticles (SPIONs) covalently bound with CdTe quantum dots (ca. 3 nm). The chemical structure of the magnetic part of BNPs is predominantly magnetite, with minor goethite and maghemite contributions, as shown by Mössbauer spectroscopy, which is compatible with the x-ray diffraction data. Their size evaluation by different techniques showed that the SPION derivatization process, in order to produce the BNPs, does not lead to a large size increase. The BNPs saturation magnetization, when corrected for the organic content of the sample, is ca. 68 emu g-1, which is only slightly reduced relative to the bare nanoparticles. This indicates that the SPION surface functionalization does not change considerably the magnetic properties. The BNP aqueous suspensions presented stability, high fluorescence, high relaxivity ratio (r 2/r 1 equal to 25) and labeled efficiently HeLa cells as can be seen by fluorescence analysis. These BNP properties point to their applications as fluorescent probes as well as negative T 2-weighted MRI contrast agents. Moreover, their potential magnetic response could also be used for fast bioseparation applications.

Synthesis, structural and spectroscopic studies of 2-oxoacenaphthylen-1(2H)-ylidene nicotinohydrazide.

The synthesis of a new hydrazone, 2-oxoacenaphthylen-1(2H)-ylidene nicotinohydrazide, and its structural and spectroscopic characterization is reported. The obtained powder was recrystallized from DMSO and ethanol that afforded small crystals used for single-crystal X-ray diffraction studies. The compound was found to crystallize in two polymorphs, depending on the crystallization conditions. One of the polymorphs (form I) crystallizes in the centrosymmetric P21/c monoclinic space group, the other (form II) crystallizes in the non-centrosymmetric, but achiral, orthorhombic space group P212121. Conformation of the molecules is similar in both polymorphs, but the network of weak intermolecular interactions determining the crystal packing is different. In form II an additional C-H⋯O bond connects molecules related by the screw-axis running parallel to the a-axis. Crystals of both polymorphs were also screened by FT-IR and Raman microscopy; a detailed analysis of the spectra and comparison with those of the isolated molecule calculated by ab-initio HF/MP2 and DFT/B3LYP methods using a correlation consistent cc-pVDZ basis set is presented. In addition, UV-vis and NMR studies were performed in solution.

5-Methylhydantoin: from Isolated Molecules in a Low-Temperature Argon Matrix to Solid State Polymorphs Characterization

The molecular structure, vibrational spectra and photochemistry of 5-methylhydantoin (C4H6N2O2; 5-MH) were studied by matrix isolation infrared spectroscopy and theoretical calculations at the DFT(B3LYP)/6-311++G(d,p) theory level. The natural bond orbital (NBO) analysis approach was used to study in detail the electronic structure of the minimum energy structure of 5-MH, namely the specific characteristics of the σ and π electronic systems of the molecule and the stabilizing orbital interactions. UV irradiation of 5-MH isolated in argon matrix resulted in its photofragmentation through a single photochemical pathway, yielding isocyanic acid, ethanimine, and carbon monoxide, thus following a pattern already observed before for the parent hydantoin and 1-methylhydantoin molecules. The investigation of the thermal properties of 5-MH was undertaken by differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM) and Raman spectroscopy. Four different polymorphs of 5-MH were identified. The crystal structure of one of the polymorphs, for which it was possible to grow up suitable crystals, was determined by X-ray diffraction (XRD). Two of the additional polymorphs were characterized by powder XRD, which confirmed the molecules pack in different crystallographic arrangements.

Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity.

Recent publications report in vitro activity of quinolone 3-esters against the bc1 protein complex of Plasmodium falciparum and the parasite. Docking studies performed in silico at the yeast Qo site established a key role for the 4-oxo and N-H groups in drug-target interactions. Thus, the possibility of 4-oxoquinoline/4-hydroxyquinoline tautomerism may impact in pharmacologic profiles and should be investigated. We describe the synthesis, structure, photochemistry, and activity against multidrug-resistant P. falciparum strain Dd2 of ethyl 4-oxo-7-methylquinoline-3-carboxylate (7Me-OQE) and ethyl 4-hydroxy-5-methylquinoline-3-carboxylate (5Me-HQE), obtained from diethyl 2-[((3-methylphenyl)amino)methylene]malonate. Theoretically (B3LYP/6-311++G(d,p)), 5Me-HQE and 7Me-OQE show clear preference for the hydroxyquinoline form. The difference between the lowest energy hydroxyquinoline and quinolone forms is 27 and 38 kJ mol(-1), for 5Me-HQE and 7Me-OQE, respectively. Calculations of aromaticity indexes show that in 5Me-HQE both rings are aromatic, while in the corresponding oxo tautomers the nitrogen-containing ring is essentially non-aromatic. The structure of monomeric 5Me-HQE was studied using matrix isolation coupled to FTIR spectroscopy. No traces of 4-oxoquinoline tautomers were found in the experimental IR spectra, revealing that the species present in the crystal, 5Me-HQE·HCl, was lost HCl upon sublimation but did not tautomerize. Continuous broadband irradiation (λ > 220 nm; 130 min) of the matrix led to only partial photodecomposition of 5Me-HQE (ca. 1/3).

On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Abstract Recent studies directed to the design of compounds targeting the bc1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol−1, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.