Daniel J. V. A. dos Santos

Lusófona University of Humanities and Technologies

P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype expressed 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 di...

Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallograph...

P-glycoprotein (P-gp, ABCB1) overexpression is, currently, one of the most important multidrug resistance (MDR) mechanisms in tumor cells. Thus, modulating drug efflux by P-gp has become one of the most promising approaches to overcome MDR in cancer. Yet, more insights on the molecular basis of drug specificity and efflux-related signal transmissio...

The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diter-penes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemi-synthesis...

A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in TMD1/NBD1 and another one in TMD2/NBD...

In this study, the impact of four P-gp mutations (G185V, G830V, F978A and ΔF335) on drug-binding and efflux-related signal-transmission mechanism was comprehensively evaluated in the presence of ligands within the drug-binding pocket (DBP), experimentally related with changes in their drug efflux profiles. The severe repacking of the transmembrane...

Protein kinase C is a family of kinases that play important roles in carcinogenesis . Medicinal plants from Plectranthus spp. (Lamiaceae) are a well-known source of interesting abietanes, such as the 7α-acetoxy-6β-hydroxyroyleanone ( Roy ). The aim of this study was to extract and isolate Roy from P. grandidentatus Gürke and compare two extraction...

Introduction Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (IAPP), or amylin, is a recognized histopathological marker of the disease. Although IAPP proteotoxicity represents an important trigger of β-cell dysfunction and ultimately...

A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBS) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in each NBD, by means of in silico fragme...

MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e.g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors overexpressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactiv...

The modulation of drug efflux by P-glycoprotein (P-gp, ABCB1) represents one of the most promising approaches to overcome multidrug resistance (MDR) in cancer cells, however the mechanisms of drug specificity and signal-transmission are still poorly understood, hampering the development of more selective and efficient P-gp modulators. In this study...

Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Comp...

Pedrolide (1), a diterpenoid with an unprecedented carbon skeleton, pedrolane, containing a bicycle[2.2.1]heptane system, is reported. This structural feature is hypothesized to involve an intramolecular cyclization, via Michael addition, and a ring contraction, via 1,2-alkyl shift or a Pinacol rearrangement of rings A and B, from a tigliane-type 5...

Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric alkaloids isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation of the indole nitrogen. Twenty-six new derivatives (3–28) were prepared by re...

Naringenin (1), isolated from Euphorbia pedroi, was previously derivatized yielding compounds 2-13. In this study, aiming at expanding the pool of analogues of the flavanone core towards better multidrug resistance (MDR) reversal agents, alkylation reactions and chemical modification of the carbonyl moiety was performed (15-39). Compounds structure...

Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6,7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6β-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectr...

N-Methyl-d-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The over-activation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for ma...

USA-Europe Data Analysis Training School (USEDAT) is a Multi-center Trans-Atlantic initiative offering hands-on training focused in both Introduction to Experimental Data Recording (NMR, MS, IR, 2DGE, EEG, etc.) and/or posterior Computational Data Analysis (Machine Learning, Complex Networks, etc.). We made emphasis on applications in for Cheminfor...

The occluded conformation suggested in a recent article that revealed a new inward-facing conformation for the human P-glycoprotein may not represent the closing of a gate region but instead an artifact derived from lateral compression in a too small sized nanodisc, used to stabilize the transmembrane domains of the transporter.

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment‐based approach to create new flexible G‐quadruplex (G4) DNA interactive small molecules with good calculated oral drug‐like properties, based on quinoline and triazole heterocycles. G4 melting temperature and Polymerase Chain Reaction‐stop assays sho...

The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2−8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, an ent-abietane diterpene, was derivatized by introduc...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Aim: Naringenin (1), isolated in large amount from the aerial parts of Euphorbia pedroi, was chemically derivatized to yield 18 imine derivatives (2-19) and three alkylated derivatives through a Mannich-type reaction (20-22) that were tested as multidrug resistance (MDR) reversers in cancer cells. Results/methodology: While hydrazone (2-4) and azi...

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective a...

P-glycoprotein (P-gp) has been considered an important molecular target in the reversal of multidrug resistance (MDR). As such, the development of P-gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies for overcoming MDR. Since the identification of the P-gp’s role in MDR, severa...

The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver...

Background: From a dataset obtained by chemical derivatization of a macrocyclic diterpenic scaffold, in silico approaches identified which structural features correlate with experimental modulation of P-gp activity. Results/methodology: Ninety-two percent of the strongest MDR modulators were positively identified within the dataset by virtual scre...

http://pubs.acs.org/doi/suppl/10.1021/acs.jctc.5b00652

The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction...

The membrane biophysical aspects by which multidrug resistance (MDR) relates with ABC transporters function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P-gp is inserted as determinant for the inc...

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][PF6]) and 1-butyl-3-methylimadazolium bis(trifluoromethylsulfonyl)imide ([BMIm][NTf2]) are herein reported. It is found that near an u...

Multidrug-resistance (MDR) phenomena is a worldwide health concern. ABC efflux pumps as P-glycoprotein (P-gp) have been thoroughly studied in a frantic run to develop new efflux modulators capable to reverse MDR phenotypes. The study of efflux pumps has provided some key aspects on drug extrusion, however the answers could not be found solely on AB...

A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent an...

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 strateg...

The effect of replacing bis(trifluoromethylsulphonyl)imide ([NTf2]) by hexafluorophosphate ([PF6]) in room temperature ionic liquid (IL) 1-butyl-3-methylimidazolium bis(trifluoromethylsulphonyl)imide ([BMIm][NTf2]) confined between two gold interfaces is herein reported through molecular dynamics simulations using all-atom non-polarisable force-fie...

One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents—multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps that are frequently involved in drug efflux from cancer cells, t...

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-,...

Cytochrome bc(1) complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. We report a molecular docking study building on the most recently obtained X-ray structure of the Sa...

This paper focuses on the importance of the intermediate linker sequence for the stabilization of the cytoplasmic portion of murine P-glycoprotein, an ABC transporter involved in Multidrug Resistance (MDR) in cancer. Three putative protein-protein interaction areas were predicted to exist, two of them next to the C-terminal nucleotide-binding domai...

The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to twelve ester derivatives (2-13) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 1-14 was evaluated through a combination of transport and chemosensitivity assays, using the L5178 mouse T lymphoma ce...

P-glycoprotein is one of the best studied transmembranar proteins directly related with multidrug resistance phenomenon. Using a refined P-gp structure recently published by our group, new docking studies have identified three distinct binding sites: two for substrates (H- and R-sites) and one for modulators (Modulator-site), which are in perfect a...

Multidrug resistance is a major hurdle for the success of cancer chemotherapy. The main cause for this phenomenon is attributed to the overexpression of the efflux pump, P-glycoprotein (P-gp). A small library of novel bioactive macrocyclic lathyrane-type diterpene derivatives was developed to discover a selective P-gp reversal agent. In this way, a...

Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of featur...

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (P-glycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and poly...

Cytochrome bc(1) is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound pr...

Cancer is one of the diseases with increased prevalence in the 21st century. Since the 1970s that a class of transmembranar proteins called ABC transporters are known, being P-Glycoprotein (Pgp) the most representative member. They are often involved in the efflux of drugs preventing their accumulation in the cytoplasm and thus decreasing the thera...

P-glycoprotein (P-gp) is the most representative member of the ABC transmembranar transporter superfamily, often implicated in the multidrug-resistance phenomenon (MDR) [1]. Several models have been proposed for the efflux mechanism, namely the hydrophobic pore, the flipase model and, more recently, the hydrophobic vacuum-cleaner model. Using the...

Allopsoralens are angular psoralen derivatives presenting advantages over the parent compound because of monofunctional DNA-photobinding and consequent lower toxicity. Allopsoralen molecules with three different substituents and different protonation states were studied using the molecular dynamics technique. The location of these molecules when in...

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...

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 P(1), as caspase-3 inhibitors. Fmoc-Val-As...