Daniel J V A dos Santos (original) (raw)
Papers by Daniel J V A dos Santos
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 13, 2014
One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. I... more One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous negative regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams and the evaluation of their biological effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compounds 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The molecular mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53(+/+)) and in its isogenic derivative without p53 (HCT116 p53(-/-)). Indeed, using these cells, we demonstrated that...
The results of a systematic molecular dynamics study of the interfacial structure between the gol... more The results of a systematic molecular dynamics study of the interfacial structure between the gold (100) surface and two room-temperature ionic liquids, namely, 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIm][PF 6 ]) and 1-butyl-3-methylimadazolium bis(trifluoromethylsulfonyl)imide ([BMIm][NTf 2 ]), are herein reported. It is found that near an uncharged surface the IL structure differs from its bulk, having an enhanced density extended until the two first layers. Interfacial layering is clearly observed at the gold surface, with a higher effect for the [BMIm][NTf 2 ] IL but a higher packing for [BMIm][PF 6 ]. In both ILs the alkyl side chains are oriented parallel to the interface while the imidazolium rings tend to be parallel to the interface in about 60% of the cases. The presence of the interface has a higher impact on the orientation of the cations than on the chemical properties of the counterion. The surface potential drop across the interface is more pronounced toward a negative value for ([BMIm][PF 6 ]) than for ([BMIm][NTf 2 ]), due to relatively larger local density of the anions for ([BMIm][PF 6 ]) near the gold surface.
European Journal of Medicinal Chemistry, 2014
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforw... more A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC 50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
European Journal of Medicinal Chemistry, 2010
The first structureeactivity relationship study of vinyl sulfones as caspase-3 inhibitors is repo... more The first structureeactivity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P 1 , as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH]CHeSO 2 Me was the most potent inhibitor of caspase-3 in the series, with a IC 50 of 29 mM and a second-order rate constant of inactivation, k inact /K i , of 1.5 M À1 s À1 .
Pharmacological Research, 2015
Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) p... more Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53+/+) and its p53-null isogenic derivative (HCT116 p53−/−), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53+/+, but not in p53−/−, HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMX-overexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53+/+ cells, the disruption of the p53 interaction with MDMs by OXAZ-1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs.
Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53–MDMs interaction.
Eur. J. Med. Chem., 2014
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforw... more A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
J. Chem. Inf. Model., 2013
P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the mul... more P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M-site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data.
J. Med. Chem., 2011
The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and t... more The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
Int. J. Quantum Chem., 2011
Cytochrome bc1 is a validated drug target of Plasmodium falciparum, the parasite that causes the ... more Cytochrome bc1 is a validated drug target of Plasmodium falciparum, the parasite that causes the most lethal form of malaria. The inhibition of cytochrome bc1 leads to the shutdown of the mitochondrial metabolism and the consequent arrest of pyrimidine biosynthesis essential for parasite development. Aiming to rationalize the stereoelectronic properties and extend the knowledge on a novel series of 4-pyridonimines guiding the search of antimalarial drugs, we carried out an extensive DFT comparative characterization. Results show electronic similarity with clopidol, a known bc1 complex inhibitor containing the 4(1H)-pyridone scaffold.
Eur. J. Med. Chem., 2010
The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is repo... more The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CHdouble bond; length as m-dashCH–SO2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M−1 s−1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CHdouble bond; length as m-dashCH–SO2Ph was inactive for caspase-7 for the tested concentrations.
Macromol. Rapid Comm., 2009
A method to compute the interfacial excess free energy of systems where a liquid phase is interac... more A method to compute the interfacial excess free energy of systems where a liquid phase is interacting with a solid phase is presented. The calculations are carried out by means of molecular dynamics simulations. The algorithm is based on a thermodynamic integration scheme that reversibly turns a flexible atomistically detailed solid surface that interacts with a liquid phase into a flat surface and allows the calculation of the variation in Gibbs free energy. The approach is probed by applying it to a model system of Lennard–Jones particles and comparing to previous calculations on similar systems.
![Research paper thumbnail of Erratum to ‘Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer’ [Chem. Phys. Lett. 463 (2008) 178]](https://attachments.academia-assets.com/37045003/thumbnails/1.jpg)
](Chem. Phys. Lett., 2009
Due to an error in an analysis program, Fig. 4A in our Letter [1] was incorrectly plotted.
Chem. Phys. Lett., 2008
5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic the... more 5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.
Int. J. Quantum Chem., 2008
The O–H and S–H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thio... more The O–H and S–H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thiophenols (NH2, OH, CH3, Cl, CF3, and NO2) have been computed by a density functional theory procedure with the 6-311++G(d,p) basis set. A very good agreement between our results and available experimental ones is observed. The effect of substituents on structure, charges and BDEs are investigated and their correlation with Hammett parameters is studied.
Chem. Phys. Lett., 2007
Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as lig... more Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as ligand were performed. The calculated interaction energies showed that the ligand can be docked into the minor groove as well as become intercalated. However, unlike psoralen, allopsoralen preferred binding mode for non-poly-TA sequences is minor groove binding. Calculated energies for intercalation between different base pairs suggest that the predicted sequence selectivity for allopsoralen is analogous to that observed for psoralen. Intercalation is favored in 5′-TpA sites in poly-TA sequences.
Research Letters in Physical Chemistry, 2007
Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecu... more Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.
J. Phys. Chem. B, 2004
We report a study on the effects of the amount of oil (100, 300, and 1372 1,2-dichloroethane mole... more We report a study on the effects of the amount of oil (100, 300, and 1372 1,2-dichloroethane molecules) spread on a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed on water. There are some related experimental results, namely, by neutron reflection on the Langmuir interface (air/water interface), that could be used carefully to understand the behavior of monolayers adsorbed at liquid/liquid interfaces. With this work we make a bridge between the Langmuir and the liquid/liquid interfaces. The addition of a small amount of DCE molecules changes dramatically various properties, namely, the distribution of the width of the chains, the distribution of the distance between the chain heads and tails, and the distribution of the tilt angle. On the other hand, the in-plane mean square distribution and the diffusion coefficient of the nitrogen atom are very similar in the systems studied, except for the system containing the largest amount of DCE molecules, which corresponds to the water/DCE interface.
Langmuir, 2003
We have simulated a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed at the water/air... more We have simulated a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed at the water/air and water/1,2-dichloroethane (DCE) interfaces. A diffusive electrical double layer was found formed by the chloride and CTA ions. It was found that the water molecules change their dipole orientation to help on the neutralization of this electrical charged layer. The DCE molecules penetrate the CTA tails and an increased concentration exists inside the tails. The tilt angle maximum probability for the CTA tails is 20° at the water/DCE interface, while at the water/air interface the maximum probability is located at 40°. The average tilt angle values are 27° and 40°, respectively. The average number of trans conformations per chain is similar at both interfaces with a maximum probability corresponding to 12 trans conformations. Nevertheless, the percentage of trans conformations in the chains is greater for the water/DCE interface and consequently the CTA tails at the water/air interface are more folded, present more defects, and are less stretched. The distribution of the chains is broader when the monolayer is adsorbed at the water/DCE interface. The motion in the monolayer plane of the terminal methyl group is less at the water/DCE interface.
Progress in Colloid and Polymer Science, 2004
The main purpose of this article is to understand at the microscopic level the possible effect of... more The main purpose of this article is to understand at the microscopic level the possible effect of the chain length on the properties of an adsorbed monolayer between two immiscible liquids. We report a molecular dynamics simulation study of an alkyltrimethylammonium chloride monolayer adsorbed in the water/isooctane interface. The surfactants studied have 8, 12 and 16 carbon atoms in the chain and are studied at a constant area of 45 Å2 per surfactant. It was found that the chain widths of the number density profile distributions increase with the chain length and the tilt angle distribution does not change with the chain length. There is also no correlation between the percentage of trans conformations in an alkyltrimethylammonium chain and the length of the chain. The probability of finding a given number of trans conformations per chain is also similar in the three different surfactants. An increase of four methylene groups in the central part of the chain just displaces this distribution by about two trans conformations. The mean-square displacement of the terminal methyl group of the alkyltrimethylammonium chains is also very similar in the different surfactant types. Our results support the conclusions of Bell et al. [(1998) J. Phys. Chem. B 102: 218] concerning the structures of the alkyltrimethylammonium monolayers (they are very similar and independent of the chain length).
![Research paper thumbnail of Synthesis, G-Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2-b]quinolines with One, Two, or Three Basic Side Chains](https://attachments.academia-assets.com/36939820/thumbnails/1.jpg)
](ChemMedChem, 2013
G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential target... more G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2-b]quinolines mono-, di-, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5-methyl or a 7-carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7-(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter-G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c-Kit2, 10-fold selectivity for G4 over duplex DNA, and 100-fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 13, 2014
One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. I... more One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous negative regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams and the evaluation of their biological effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compounds 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The molecular mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53(+/+)) and in its isogenic derivative without p53 (HCT116 p53(-/-)). Indeed, using these cells, we demonstrated that...
The results of a systematic molecular dynamics study of the interfacial structure between the gol... more The results of a systematic molecular dynamics study of the interfacial structure between the gold (100) surface and two room-temperature ionic liquids, namely, 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIm][PF 6 ]) and 1-butyl-3-methylimadazolium bis(trifluoromethylsulfonyl)imide ([BMIm][NTf 2 ]), are herein reported. It is found that near an uncharged surface the IL structure differs from its bulk, having an enhanced density extended until the two first layers. Interfacial layering is clearly observed at the gold surface, with a higher effect for the [BMIm][NTf 2 ] IL but a higher packing for [BMIm][PF 6 ]. In both ILs the alkyl side chains are oriented parallel to the interface while the imidazolium rings tend to be parallel to the interface in about 60% of the cases. The presence of the interface has a higher impact on the orientation of the cations than on the chemical properties of the counterion. The surface potential drop across the interface is more pronounced toward a negative value for ([BMIm][PF 6 ]) than for ([BMIm][NTf 2 ]), due to relatively larger local density of the anions for ([BMIm][PF 6 ]) near the gold surface.
European Journal of Medicinal Chemistry, 2014
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforw... more A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC 50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
European Journal of Medicinal Chemistry, 2010
The first structureeactivity relationship study of vinyl sulfones as caspase-3 inhibitors is repo... more The first structureeactivity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P 1 , as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH]CHeSO 2 Me was the most potent inhibitor of caspase-3 in the series, with a IC 50 of 29 mM and a second-order rate constant of inactivation, k inact /K i , of 1.5 M À1 s À1 .
Pharmacological Research, 2015
Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) p... more Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53+/+) and its p53-null isogenic derivative (HCT116 p53−/−), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53+/+, but not in p53−/−, HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMX-overexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53+/+ cells, the disruption of the p53 interaction with MDMs by OXAZ-1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs.
Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53–MDMs interaction.
Eur. J. Med. Chem., 2014
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforw... more A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
J. Chem. Inf. Model., 2013
P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the mul... more P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M-site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data.
J. Med. Chem., 2011
The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and t... more The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
Int. J. Quantum Chem., 2011
Cytochrome bc1 is a validated drug target of Plasmodium falciparum, the parasite that causes the ... more Cytochrome bc1 is a validated drug target of Plasmodium falciparum, the parasite that causes the most lethal form of malaria. The inhibition of cytochrome bc1 leads to the shutdown of the mitochondrial metabolism and the consequent arrest of pyrimidine biosynthesis essential for parasite development. Aiming to rationalize the stereoelectronic properties and extend the knowledge on a novel series of 4-pyridonimines guiding the search of antimalarial drugs, we carried out an extensive DFT comparative characterization. Results show electronic similarity with clopidol, a known bc1 complex inhibitor containing the 4(1H)-pyridone scaffold.
Eur. J. Med. Chem., 2010
The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is repo... more The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CHdouble bond; length as m-dashCH–SO2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M−1 s−1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CHdouble bond; length as m-dashCH–SO2Ph was inactive for caspase-7 for the tested concentrations.
Macromol. Rapid Comm., 2009
A method to compute the interfacial excess free energy of systems where a liquid phase is interac... more A method to compute the interfacial excess free energy of systems where a liquid phase is interacting with a solid phase is presented. The calculations are carried out by means of molecular dynamics simulations. The algorithm is based on a thermodynamic integration scheme that reversibly turns a flexible atomistically detailed solid surface that interacts with a liquid phase into a flat surface and allows the calculation of the variation in Gibbs free energy. The approach is probed by applying it to a model system of Lennard–Jones particles and comparing to previous calculations on similar systems.
Chem. Phys. Lett., 2009
Due to an error in an analysis program, Fig. 4A in our Letter [1] was incorrectly plotted.
Chem. Phys. Lett., 2008
5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic the... more 5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.
Int. J. Quantum Chem., 2008
The O–H and S–H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thio... more The O–H and S–H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thiophenols (NH2, OH, CH3, Cl, CF3, and NO2) have been computed by a density functional theory procedure with the 6-311++G(d,p) basis set. A very good agreement between our results and available experimental ones is observed. The effect of substituents on structure, charges and BDEs are investigated and their correlation with Hammett parameters is studied.
Chem. Phys. Lett., 2007
Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as lig... more Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as ligand were performed. The calculated interaction energies showed that the ligand can be docked into the minor groove as well as become intercalated. However, unlike psoralen, allopsoralen preferred binding mode for non-poly-TA sequences is minor groove binding. Calculated energies for intercalation between different base pairs suggest that the predicted sequence selectivity for allopsoralen is analogous to that observed for psoralen. Intercalation is favored in 5′-TpA sites in poly-TA sequences.
Research Letters in Physical Chemistry, 2007
Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecu... more Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.
J. Phys. Chem. B, 2004
We report a study on the effects of the amount of oil (100, 300, and 1372 1,2-dichloroethane mole... more We report a study on the effects of the amount of oil (100, 300, and 1372 1,2-dichloroethane molecules) spread on a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed on water. There are some related experimental results, namely, by neutron reflection on the Langmuir interface (air/water interface), that could be used carefully to understand the behavior of monolayers adsorbed at liquid/liquid interfaces. With this work we make a bridge between the Langmuir and the liquid/liquid interfaces. The addition of a small amount of DCE molecules changes dramatically various properties, namely, the distribution of the width of the chains, the distribution of the distance between the chain heads and tails, and the distribution of the tilt angle. On the other hand, the in-plane mean square distribution and the diffusion coefficient of the nitrogen atom are very similar in the systems studied, except for the system containing the largest amount of DCE molecules, which corresponds to the water/DCE interface.
Langmuir, 2003
We have simulated a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed at the water/air... more We have simulated a hexadecyltrimethylammonium (CTA) chloride monolayer adsorbed at the water/air and water/1,2-dichloroethane (DCE) interfaces. A diffusive electrical double layer was found formed by the chloride and CTA ions. It was found that the water molecules change their dipole orientation to help on the neutralization of this electrical charged layer. The DCE molecules penetrate the CTA tails and an increased concentration exists inside the tails. The tilt angle maximum probability for the CTA tails is 20° at the water/DCE interface, while at the water/air interface the maximum probability is located at 40°. The average tilt angle values are 27° and 40°, respectively. The average number of trans conformations per chain is similar at both interfaces with a maximum probability corresponding to 12 trans conformations. Nevertheless, the percentage of trans conformations in the chains is greater for the water/DCE interface and consequently the CTA tails at the water/air interface are more folded, present more defects, and are less stretched. The distribution of the chains is broader when the monolayer is adsorbed at the water/DCE interface. The motion in the monolayer plane of the terminal methyl group is less at the water/DCE interface.
Progress in Colloid and Polymer Science, 2004
The main purpose of this article is to understand at the microscopic level the possible effect of... more The main purpose of this article is to understand at the microscopic level the possible effect of the chain length on the properties of an adsorbed monolayer between two immiscible liquids. We report a molecular dynamics simulation study of an alkyltrimethylammonium chloride monolayer adsorbed in the water/isooctane interface. The surfactants studied have 8, 12 and 16 carbon atoms in the chain and are studied at a constant area of 45 Å2 per surfactant. It was found that the chain widths of the number density profile distributions increase with the chain length and the tilt angle distribution does not change with the chain length. There is also no correlation between the percentage of trans conformations in an alkyltrimethylammonium chain and the length of the chain. The probability of finding a given number of trans conformations per chain is also similar in the three different surfactants. An increase of four methylene groups in the central part of the chain just displaces this distribution by about two trans conformations. The mean-square displacement of the terminal methyl group of the alkyltrimethylammonium chains is also very similar in the different surfactant types. Our results support the conclusions of Bell et al. [(1998) J. Phys. Chem. B 102: 218] concerning the structures of the alkyltrimethylammonium monolayers (they are very similar and independent of the chain length).
ChemMedChem, 2013
G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential target... more G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2-b]quinolines mono-, di-, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5-methyl or a 7-carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7-(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter-G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c-Kit2, 10-fold selectivity for G4 over duplex DNA, and 100-fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.