Conformational stability of ibuprofen: Assessed by DFT calculations and optical vibrational spectroscopy

A thorough conformational analysis of ibuprofen [2-(4-isobutylphenyl) propionic acid] was carried by out, using density functional theory (DFT) calculations coupled to optical vibrational spectroscopy (both Raman and FTIR). Eight different geometries were found to be energy minima. The relative orientations of the substituent groups in the ibuprofen molecule, which can be considered as a para-substituted phenyl ring, were verified to hardly affect its conformational stability. The internal rotations converting the calculated conformers of ibuprofen were studied and the intramolecular interactions governing the conformational preferences of the molecule were analyzed by quantitative potential energy deconvolution using Fourier type profiles. The harmonic vibrational frequencies and corresponding intensities were calculated for all the conformers obtained, leading to the assignment of the spectra, and evidencing the sole presence of one of the lowest energy conformers in the solid state. Vibrational spectroscopic proof of intermolecular hydrogen bonds between the carboxylic groups of adjacent ibuprofen molecules, leading to the formation of dimers, was also obtained. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:845-859, 200

Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy

Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 μM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents

Drug–excipient interactions in ketoprofen: A vibrational spectroscopy study

Ketoprofen (3-benzoyl-alpha-methylbenzeneacetic acid) is a widely used nonsteroidal anti-inflammatory drug (NSAID), always administered in the form of drug-excipient physical mixtures (PMs). The occurrence of possible interactions between ketoprofen and two commonly used excipients-lactose (LAC) and polyvinylpyrrolidone (PVP)-was evaluated, through vibrational spectroscopy techniques [both Raman and Inelastic Neutron Scattering (INS)]. Spectral evidence of drug:excipient close contacts, which were enhanced by aging, was verified for the (1:1) (w:w) (ketoprofen:PVP) and (ketoprofen:LAC) PMs, both by Raman and INS. These interactions were found to involve mainly the central carbonyl and the terminal methyl-carboxylic moieties of the ketoprofen molecule, this being reflected in particular vibrational modes, such as the methyl torsion, the out-of-plane C-OH bending, and the inter-ring C=O stretching

Study of carvedilol by combined Raman spectroscopy and ab initio MO calculations

The novel cardioprotective drug carvedilol was studied by both Raman spectroscopy and ab initio molecular orbital methods (using the density functional theory approach). The spectra, acquired both for the solid samples and DMSO solutions as a function of pH, were assigned in view of the calculated wavenumbers and intensities, and also based on the experimental data obtained for individual compounds which comprise the molecule, namely carbazole and 1,2-dimethoxybenzene. The pH dependence of the Raman pattern of carvedilol was studied, and the pKa value of its secondary amine group was determined (pKa = 8.25) through pH titration experiments. This kind of information is of great significance for the understanding of the biochemical role of carvedilol, which is strongly determined by the acid-base behaviour of the molecule. Copyright © 2002 John Wiley & Sons, Ltd

Influence of Cellulose Ether Mixtures on Ibuprofen Release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades—methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively—were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.http://www.informaworld.com/10.1080/1083745060056134

A conformational study of hydroxylated isoflavones by vibrational spectroscopy coupled with DFT calculations

The conformational preferences of a series of hydroxylated isoflavones were studied by optical vibrational spectroscopy (FTIR and Raman) coupled with density functional theory (DFT) calculations. Special attention was paid to the effect of the hydroxyl substitution, due to the importance of this group in the biological activity of these systems. The isoflavones investigated – daidzein, genistein and formononetin – were shown to exist in distinct conformations in the solid state, namely regarding the orientation of the hydroxylic groups at C7 and within the catechol moiety, that are determinant factors for their conformational behaviour and antioxidant ability. In the light of the most stable conformers obtained for each molecule, a complete assignment of their experimental vibrational spectra was performed

Tabelas de esperança de vida e fertilidade de Myzus persicae sobre pimentão em laboratório e casa de vegetação.

Estudos de tabelas de vida de insetos-praga em diferentes temperaturas auxiliam na compreensão da dinâmica populacional desses organismos. Objetivou-se calcular tabelas de esperança de vida e de fertilidade de Myzus persicae criado em pimentão Capsicum annuum, em diferentes condições térmicas. O estudo foi realizado em câmaras climatizadas, nas temperaturas de 15, 20, 25 e 30 ºC, UR de 70±10% e fotofase de 12 horas, e em casa de vegetação em temperaturas oscilantes, com média de 24,9 ºC e UR de 68,1%. A longevidade máxima de adultos de M. persicae foi maior a 15 ºC (45 dias) e diminuiu a 20 ºC (39 dias), 25 ºC (27 dias), 30 ºC (24 dias) e, em casa de vegetação a 24,9 ºC foi de 29,5 dias. A esperança de vida (ex) no primeiro dia de observação foi de 43,76; 35,39; 21,44; 17,67 e 17,03 dias, para as ninfas mantidas a 15, 20, 25, 30 e 24,9 ºC respectivamente, tendo a partir daí uma queda acentuada até o fim das observações. Os parâmetros de tabelas de vida e de fertilidade evidenciaram que a temperatura de 25 ºC proporcionou a melhor condição térmica para o crescimento populacional de M. persicae, com maior capacidade de aumentar em número (rm = 0,31) e menor tempo necessário para a população duplicar (TD=2,22 dias). Em casa de vegetação a oscilação térmica afetou o crescimento populacional, proporcionando menor valor de rm (0,28) e maior TD (2,47 dias), comparados àqueles mantidos à temperatura constante equivalente

A novel approach in glioblastoma multiforme drug discovery: Perturbation studies in vitro

Despite impressive advances in drug discovery methods, predicting cellular response to anticancer drugs remains challenging. In glioblastoma multiforme, this fact is even marked as many promising drugs were followed by disappointment. As a result, the aim of this study is to clarify the effects of inhibition of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in glioblastoma multiforme, while exploring how the focus on potency might ignore the potential impact of variation in other pharmacological parameters. The evaluation of the induced drug perturbation in glioblastoma cancer cells and a multiparametric characterization dose-response of two PDK1 inhibitors were performed. Singular analysis of potency would lead to the conclusion that FC100 compound would be the most promising to treat glioblastoma multiforme. However, exploring other pharmacological parameters shows the opposite giving more information about the cell response. The study shows that potency should not be the critical factor in developing new drugs as our most potent compound lacks growth inhibition effect. So, the evaluation of promising drugs during the drug discovery phase needs to be re-evaluated and multiparametric dose-response analysis might be a useful approach to compare drugs and potentially better characterization of both drug and disease profiles