Jordi Teixidó

Porphycenes: Facts and Prospects in Photodynamic Therapy of Cancer

The photodynamic process induces cell damage and death by the combined effect of a photosensitizer (PS), visible light, and molecular oxygen, which generate singlet oxygen ((1)O(2)) and other reactive oxygen species that are responsible for cytotoxicity. The most important application of this process with increasing biomedical interest is the photodynamic therapy (PDT) of cancer. In addition to hematoporphyrin-based drugs, 2nd generation PSs with better photochemical properties are now studied using cell cultures, experimental tumors and clinical trials. Porphycene is a structural isomer of porphyrin and constitutes an interesting new class of PS. Porphycene derivatives show higher absorption than porphyrins in the red spectral region (lambda > 600 nm, epsilon > 50000 M-(1)cm(-1)) owing to the lower molecular symmetry. Photophysical and photobiological properties of porphycenes make them excellent candidates as PSs, showing fast uptake and diverse subcellular localizations (mainly membranous organelles). Several tetraalkylporphycenes and the tetraphenyl derivative (TPPo) induce photodamage and cell death in vitro. Photodynamic treatments of cultured tumor cells with TPPo and its palladium(II) complex induce cytoskeletal changes, mitotic blockage, and dose-dependent apoptotic or necrotic cell death. Some pharmacokinetic and phototherapeutic studies on experimental tumors after intravenous or topical application of lipophilic alkyl-substituted porphycene derivatives are known. Taking into account all these features, porphycene PSs should be very useful for PDT of cancer and other biomedical applications.

Comparison of Ligand-Based and Receptor-Based Virtual Screening of HIV Entry Inhibitors for the CXCR4 and CCR5 Receptors Using 3D Ligand Shape Matching and Ligand−Receptor Docking

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 co-receptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these co-receptors and, hence, ultimately block virus-cell fusion. This article describes a detailed comparison of the performance of receptor-based and ligand-based virtual screening approaches to find CXCR4 and CCR5 antagonists that could potentially serve as HIV entry inhibitors. Because no crystal structures for these proteins are available, homology models of CXCR4 and CCR5 have been built, using bovine rhodopsin as the template. For ligand-based virtual screening, several shape-based and property-based molecular comparison approaches have been compared, using high-affinity ligands as query molecules. These methods were compared by virtually screening a library assembled by us, consisting of 602 known CXCR4 and CCR5 inhibitors and some 4700 similar presumed inactive molecules. For each receptor, the library was queried using known binders, and the enrichment factors and diversity of the resulting virtual hit lists were analyzed. Overall, ligand-based shape-matching searches yielded higher enrichments than receptor-based docking, especially for CXCR4. The results obtained for CCR5 suggest the possibility that different active scaffolds bind in different ways within the CCR5 pocket.

A three-component synthesis of pyrido[2,3-d]pyrimidines

Abstract A new, high yield multicomponent reaction providing multifunctionalized pyrido[2,3- d ]pyrimidines in a microwave-assisted one-pot cyclocondensation of α,β-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is described (the ‘Victory’ reaction).

APIF: A New Interaction Fingerprint Based on Atom Pairs and Its Application to Virtual Screening

A new interaction fingerprint (IF) called APIF (atom-pairs-based interaction fingerprint) has been developed for postprocessing protein-ligand docking results. Unlike other existing fingerprints which employ absolute locations of individual interactions, APIF considers the relative positions of pairs of interacting atoms. Docking-based virtual screening was performed with GOLD using the crystal structures of trypsin, rhinovirus, HIV protease, carboxypeptidase, and estrogen receptor-alpha as targets. A score derived from the similarity of the bit strings for each docking solution to that of a known reference binding mode was obtained. Comparisons between APIF, GoldScore function, and standard interaction fingerprint (CHIF) scores were performed using enrichment plots. Superior recovery rates were observed in the IF score cases. Comparable results were achieved by using either of the two interaction fingerprints, substantially improving GoldScore function enrichment factors. Binding mode analyses were also carried out in order to study the best method for selecting conformations with a binding mode similar to that of the reference crystallized complex. These showed that the first conformations retrieved by interaction fingerprint scores had a more similar binding mode to the reference complex than those retrieved by the GoldScore function.

Synthesis of 2,7,12,17-tetraphenylporphycene (TPPo). First aryl-substituted porphycene for the photodynamic therapy of tumors

Abstract We report on the synthesis of 2,7,12,17-tetraphenylporphycene (TPPo), the first example of an aryl-substituted porphycene macrocycle. A modification of the general porphycene synthetic method has been used, thus avoiding an intermediate sublimation. TPPo has an absorption maximum at 659 nm ( e = 50.000 M −1 cm −1 ), and shows good sensitizing properties: it photoproduces singlet oxygen with a quantum yield of ca. 0.25, is phototoxic to cells, and has low dark toxicity. These properties make TPPo a suitable candidate for the photodynamic therapy of tumors.

A comparison between the photophysical and photosensitising properties of tetraphenyl porphycenes and porphyrins

The photophysical properties of 2,7,12,17-tetraphenylporphycene (TPPo) and its palladium(II) (PdTPPo) and copper(II) (CuTPPo) complexes as well as comparisons with those of their porphyrin counterparts are reported. All porphycenes absorb in the red part of the spectrum, but only TPPo shows fluorescence (ΦF = 0.15). This compound presents good quantum yields of triplet (ΦT = 0.33) and singlet oxygen (ΦΔ = 0.23) formation. In the case of PdTPPo, fluorescence is inhibited by the internal heavy-atom effect and the triplet and singlet oxygen quantum yields are enhanced (ΦT = ΦΔ = 0.78). The presence of the paramagnetic ion Cu(II) in CuTPPo further enhances the non-radiative transitions leading to an internal conversion quantum yield Φic = 0.65 and to a triplet quantum yield ΦT = 0.35. With a triplet lifetime of 700 ns, CuTPPo is nevertheless able to sensitise singlet oxygen with a quantum yield that strongly depends on the oxygen concentration in the environment. These photophysical properties, together with their ability to kill several cancer cell lines, place these sensitisers in a good position to be used in photodynamic therapy (PDT).

Solid-supported synthetic equivalents of 3-formylchromone and chromone

Abstract Treatment of bound o -hydroxyacetophenone 10 under Vilsmeier–Haack reaction conditions yields 11a or 12b , synthetic equivalents of 3-formylchromone ( 1 ) and chromone ( 13 ) respectively, depending on the resin used as solid support (Merrifield or Wang chloro resin respectively).

Cavitation contribution to the free energy of solvation.: Comparison of different formalisms in the context of MST calculations

Abstract We present a systematic study on the contribution of the cavitation term to the solvation free energy of a series of small neutral molecules. Different approaches to the calculation of the cavitation term in MST–SCRF calculations of the solvation free energy are analyzed. Optimum van der Waals parameters to be used with different definitions of cavitation contributions are obtained for water, chloroform and carbon tetrachloride.

Clustering and Classifying Diverse HIV Entry Inhibitors Using a Novel Consensus Shape-Based Virtual Screening Approach : Further Evidence for Multiple Binding Sites within the CCR5 Extracellular Pocket

HIV entry inhibitors have emerged as a new generation of antiretroviral drugs that block viral fusion with the CXCR4 and CCR5 membrane coreceptors. Several small molecule antagonists for these coreceptors have been developed, some of which are currently in clinical trials. However, because no crystal structures for the coreceptor proteins are available, the binding modes of the known inhibitors within the coreceptor extracellular pockets need to be analyzed by means of site-directed mutagenesis and computational experiments. Previous studies have indicated that there is more than one binding site within the CCR5 extracellular pocket. This article investigates and develops this hypothesis using a novel spherical harmonic-based consensus shape clustering approach. The consensus shape approach is evaluated using retrospective virtual screening of CXCR4 and CCR5 inhibitors. Multiple combinations of CCR5 ligands in multiple trial superpositions are constructed to find consensus queries that give high virtual screening enrichments. Receiver-operator-characteristic performance analyses for both CXCR4 and CCR5 inhibitors show that the new consensus shape matching approach gives better virtual screening enrichments than existing shape matching and docking virtual screening techniques. The results obtained also provide strong evidence to support the notion that there are three main binding sites within the CCR5 extracellular cavity.

Discovery of Novel HIV Entry Inhibitors for the CXCR4 Receptor by Prospective Virtual Screening

The process of HIV entry begins with the binding of the viral envelope glycoprotein gp120 to both the CD4 receptor and one of CXCR4 or CCR5 chemokine coreceptors. There is currently considerable interest in developing novel ligands which can attach to these coreceptors and hence block virus-cell fusion. This article compares the application of structure-based (docking) and ligand-based (QSAR analyses, pharmacophore modeling, and shape matching) virtual screening tools to find new potential HIV entry inhibitors for the CXCR4 receptor. The comparison is based on retrospective virtual screening of a library containing different known CXCR4 inhibitors from the literature, a smaller set of active CXCR4 inhibitors selected from a large combinatorial virtual library and synthesized by us, and some druglike presumed inactive molecules as the reference set. The enrichment factors and diversity of the retrieved molecular scaffolds in the virtual hit lists was determined. Once the different virtual screening approaches had been validated and the best parameters had been selected, prospective virtual screening of our virtual library was applied to identify new anti-HIV compounds using the same protocol as in the retrospective virtual screening analysis. The compounds selected using these computational tools were subsequently synthesized and assayed and showed activity values ranging from 4 to 0.022 microg/mL.