Mariana Matias - Academia.edu (original) (raw)

Papers by Mariana Matias

Pharmaceutics

Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, ... more Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, affecting about 50 million people worldwide. Pharmacological therapy has been, and is likely to remain, the main treatment approach for this disease. Although a large number of new antiseizure drugs (ASDs) has been introduced into the market in the last few years, many patients suffer from uncontrolled seizures, demanding the development of more effective therapies. Nanomedicines have emerged as a promising approach to deliver drugs to the brain, potentiating their therapeutic index. Moreover, nanomedicine has applied the knowledge of nanoscience, not only in disease treatment but also in prevention and diagnosis. In the current review, the general features and therapeutic management of epilepsy will be addressed, as well as the main barriers to overcome to obtain better antiseizure therapies. Furthermore, the role of nanomedicines as a valuable tool to selectively deliver drugs will be ...

Applied Sciences , 2022

C-Ring oxidized estrone acetate derivatives as antiproliferative agents were prepared and tested ... more C-Ring oxidized estrone acetate derivatives as antiproliferative agents were prepared and tested against five cancer cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry assays to evaluate cell viability and modifications in cell cycle phases and molecular docking research against estrogen receptor α, steroid sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 were performed. 9α-Hydroxy,11β-nitrooxyestrone acetate was the most cytotoxic molecule against hormone-dependent cancer cells. Furthermore, flow cytometry experiments revealed that this 9α-hydroxy,11β-nitrooxy derivative markedly reduced HepaRG cells viability (~92%) after 24 h of treatment. However, 9α-hydroxyestrone acetate led to selective inhibition of HepaRG cells growth, inducing a G0/G1 cycle arrest, and did not originate a proliferation effect on T47-D cancer cells. Docking studies estimated a generally lower affinity of these compounds to estrogen receptor α than predicted for estrone and 17β-estradiol. Therefore, this structural modification can be of interest to develop new anticancer estrane derivatives devoid of estrogenic action.

European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences , 2017

The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, bu... more The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood-brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM. The in vitro results suggested that 82% of the test compounds have good intestinal permeability (Papp>1.1×10(-6)cm/s), and 66% of these are also expected to exhibit good permeability through blood-brain barrier (Papp>2.0×10(-6)cm/s); these findings are consistent with a high transport rate by passive transcellular pathway. In both PAMPA models, thiourea derivatives presented higher Papp values than the respective urea analogues, which were further corroborated by in silico predictions. The in vitro results also suggested a low extent of plasma protein binding for all compounds (Papp<1.0×10(-5)cm/s), and these findings were also supported by in silico data (unbound fraction ranging from 0.13 to 0.59). In addition, although approximately half of the compounds did not modulate P-gp at the tested concentrations (10 and 50μM), nine of them presented a trend to induce P-gp and particularly the chlorinated compounds exhibited a marked P-gp inhibition at 50μM. Furthermore, the in silico predictions suggested that half of the compounds have hepatotoxic potential. Overall, within this group of compounds the thiourea derivatives containing an unsubstituted or a monosubstituted (NO2, CH3, OCH3) phenyl ring attached to the position 4 of the dihydropyrimidine ring represented the most promising structures and should be considered in the subsequent studies of the development of new structurally related drug candidates.

European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences , 2017

Although significant advances are occurring in epilepsy research, about 30% of epileptic patients... more Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests. The results of preliminary pharmacological screening after intraperitoneal injection in mice revealed that twenty-four compounds showed protection in half or more of the animals tested in the MES seizure model, being nine of them active at the lowest dose tested (30 mg/kg). Structurally, the most promising compounds (both urea and thiourea derivatives) presented smaller lateral chains and unsubstituted or para-substituted phenyl ring with a methyl group. Compounds 4, 5 and 11 also protected against MES-induced seizures in 50–75% of rats after oral administration at 30 mg/kg. Moreover, the minimal motor and/or neurological impairment evaluated through the rotarod assay showed that around 52% of the compounds presented lower toxicity than the antiepileptic drugs lamotrigine, carbamazepine and phenytoin. In addition, the most active compounds did not show notable cytotoxicity in in vitro experiments conducted in several cell lines (relative cell proliferation higher than 50% at 30 μM), which can be relevant due to the fact that the toxicity is a common problem of the available antiepileptic drugs. Furthermore, additional computational studies indicated that all compounds respected the Lipinski's rule of five, which, together with the data of efficacy and toxicity, make them attractive compounds to be developed in the future as potential anticonvulsant agents.

Mini Reviews in Medicinal Chemistry , 2016

Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing... more Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides, such as enkephalins, deltorphin and endomorphin, have been developed and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control. In addition, as potential antiepileptic drugs, a lot of compounds targeting primarily the GABAergic pathways have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity. Moreover, hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing antioxidant hybrid compounds which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2016

Background: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in ... more Background: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in folk medicine. Due to the claimed anticonvulsant properties of G. elata, it is expected that this herb continues to be a target of research, aiming to deepen the available knowledge on its biological activity and safety. Purpose: The current review aims to discuss the most recent advances on the elucidation of the phytochemical composition and anticonvulsant potential of G. elata. Methods: Available literature was reviewed from PubMed, ISI Web of Knowledge and Science Direct, using combinations of the following keywords: Gastrodia elata, tianma, epilepsy, anticonvulsant and pharmacokinetics. Abstracts and full texts were evaluated for their clarity and scientific merit. Results: G. elata rhizome, as well as specific phenolic compounds isolated from this herb, have demonstrated anticonvulsant potential in a variety of in vitro and in vivo models. The pharmacological mechanisms potentially involved in the anticonvulsant activity have been extensively studied, being similar to the known mechanisms claimed for the available antiepileptic drugs. In addition, the pharmacokinetics of the main bioactive component of G. elata (gastrodin) has also been studied. Conclusion: Due to its recognised therapeutic properties, G. elata has gained an increasing interest within the scientific community and, therefore, new medicinal preparations containing G. elata rhizome itself or its bioactive components are expected to be developed in the coming years. Moreover, specific phytochemical constituents isolated from G. elata may also be considered to integrate programs of discovery and development of new anticonvulsant drug candidates.

Molecules, 2021

The interest in the introduction of the oxime group in molecules aiming to improve their biologic... more The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.

Drug Delivery and Translational Research, 2021

Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major... more Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major cause of cancer-associated deaths. Surgical resection is considered the standard therapeutic choice for CC in early stages. However, in latter stages of the disease, adjuvant chemotherapy is essential for an appropriate management of this pathology. Metal-based complexes displaying cytotoxic properties towards tumor cells emerge as potential chemotherapeutic options. One metallodrug, oxaliplatin, was already approved for clinical use, playing an important role in the treatment of CC patients. Unfortunately, most of the newly designed metal-based complexes exhibit lack of selectivity against cancer cells, low solubility and permeability, high dose-limiting toxicity, and emergence of resistances. Nanodelivery systems enable the incorporation of metallodrugs at adequate payloads, solving the above-referred drawbacks. Moreover, drug delivery systems, depending on their physicochemical properties, are able to release the incorporated material preferentially at affected tissues/organs, enhancing the therapeutic activity in vivo, with concomitant fewer side effects. In this review, the general features and therapeutic management of CC will be addressed, with a special focus on preclinical or clinical studies using metal-based compounds. Furthermore, the use of different nanodelivery systems will also be described as tools to potentiate the therapeutic index of metallodrugs for the management of CC.

Natural Product Research , 2022

10β-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotec... more 10β-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotective activity. However, the cytotoxic properties of this quinol are barely studied. Thus, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF). Additionally, an in vitro estrogenicity assay and a cell viability analysis together with in silico molecular docking studies were carried out in order to understand the potential mechanism of cytotoxicity. Computational predictions of its pharmacokinetic and toxicity properties were also performed. Surprisingly, HEDD displayed marked cytotoxic activity, particularly against hormone-dependent cancer cells and the flow cytometry analysis revealed that HEDD markedly reduced the viability of hepatic cancer cells. Molecular docking studies suggested a high affinity towards the estrogen receptor α and 17β-hydroxysteroid dehydrogenase type 1. Moreover, it was predicted that HEDD may have good oral bioavailability and a low maximum tolerated dose in humans.

Cells, 2021

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resista... more Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

Journal of Pharmacy and Pharmaceutical Sciences, 2018

During the discovery and development of new drugs, compounds with low aqueous solubility pose spe... more During the discovery and development of new drugs, compounds with low aqueous solubility pose special challenges in their pharmacological evaluation and, therefore, the selection of appropriate vehicles to administer the compounds of interest is determinant for the quality of the results generated during the in vivo non-clinical studies. This work aimed to evaluate the motor deficit (as a surrogate of neurotoxicity) of several administration/delivery vehicles through the rotarod performance test. Methods-Trained male CD-1 mice were intraperitoneally administered with the following vehicles: dimethyl sulfoxide (DMSO), aqueous sodium chloride (NaCl) 0.9%, aqueous carboxymethylcellulose (CMC) 0.5%, polyethylene glycol (PEG)-400, propylene glycol (PG), and solutions of these vehicles containing 5% and 10% DMSO. Results-It was observed that the aqueous vehicles (NaCl 0.9% and CMC 0.5%) did not affect the performance of the animals on the rod. On the other hand, a vehicle consisting solely of DMSO led to significant motor impairment and only a small improvement was recorded over time. Additionally, a strong neuromotor toxicity was observed in the early evaluation points of the experiment using vehicles constituted by PG and PEG-400 or by mixtures of PG/DMSO (5% and 10%) and PEG-400/DMSO (5% and 10%). Conclusion-This study provides useful data about the neurotoxicity inherent to several vehicles frequently used in non-clinical pharmaco-toxicological assays, aiming to draw especial attention to the need of a careful selection of drug vehicles in order to avoid the impact of such confounding variables on the accuracy of the results and in decision-making processes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Comptes Rendus Chimie , 2020

A series of D9,11-estrone derivatives with A- and D-ring modifications has been synthesized and e... more A series of D9,11-estrone derivatives with A- and D-ring modifications has been synthesized and evaluated as antiproliferative agents. The cytotoxicity was assessed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and a cell cycle distribution analysis was performed by flow cytometry. Some compounds exhibited relevant cytotoxicity, particularly D9,11-estrone, which was the most active against HepaRG cells (IC50 = 6.67 uM). Besides the relevance of the double bond in the C-ring, the presence of a 16E-benzylidene group increased the antiproliferative effect on MCF-7 and T47-D cells. Moreover, the introduction of iodine in positions 2 and 4 of estrone seemed to induce a selective cytotoxicity for HepaRG cells. Flow cytometry experiments evidenced a 34% reduction of HepaRG cell viability after treatment with D9,11-estrone and a cell cycle arrest at the phase. Estrogenic activity was also observed for this compound at 0.1 uM in T47-D cells, and molecular docking studies estimated a marked interaction between this compound and the estrogen receptor alfa.

Nanomaterials, 2019

Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. T... more Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. The current treatment options involve surgery, radiotherapy, targeted therapy, immunotherapy and the use of chemotherapeutic agents. Although the last approach is the most used, the high toxicity and the lack of efficacy in advanced stages of the disease have demanded the search for novel bioactive molecules and/or efficient drug delivery systems. The current review aims to discuss the most recent advances on the elucidation of potential targets for melanoma treatment, such as aquaporin-3 and tyrosinase. In addition, the role of nanotechnology as a valuable strategy to effectively deliver selective drugs is emphasized, either incorporating/encapsulating synthetic molecules or natural-derived compounds in lipid-based nanosystems such as liposomes. Nanoformulated compounds have been explored for their improved anticancer activity against melanoma and promising results have been obtained. Indeed, they displayed improved physicochemical properties and higher accumulation in tumoral tissues, which potentiated the efficacy of the compounds in pre-clinical experiments. Overall, these experiments opened new doors for the discovery and development of more effective drug formulations for melanoma treatment.

Arabian Journal of Chemistry, 2019

A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1-22) was synthesized through the Biginelli reac... more A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1-22) was synthesized through the Biginelli reaction in order to find novel anticancer drug candidates based on the structure of monastrol. The antiproliferative activity of the compounds was screened in several cell lines and the chlorinated compounds expressed considerable cytotoxicity in hepatic and/or colon and MCF-7 breast cancer cell lines. Within these, compound 11 was the most potent and showed strong antiproliferative effects on HepaRG cells (IC50 = 0.75 μM). Using cell proliferation data, a quantitative structure-activity relationship (QSAR) analysis was performed employing Bayesian regularized artificial neural networks to relate in silico calculated molecular descriptors and bioactivity of the compounds across the tested cell lines. A statistical valid QSAR model was obtained, which allows the prediction of the relative cell proliferation for hypothetical analogous compounds in the studied cell lines. Additionally, cell cycle distribution analysis showed that another potent chlorinated molecule, compound 15, caused accumulation of cells in G0/G1 phase of the cell cycle in HepaRG and MCF-7 cells, which suggests a distinct mechanism of action relatively to monastrol. Overall, chlorinated monastrol analogues showed potent cytotoxic activity in cancer cells and deserve further investigation to ascertain their potential as candidate anticancer agents.

RSC Advances, 2016

The search for novel anticancer agents with higher selectivity and lower toxicity remains a prior... more The search for novel anticancer agents with higher selectivity and lower toxicity remains a priority. This work aimed to design more potent and selective anticancer molecules among the class of 3,4-dihydropyrimidin-2-(1H)-ones. Thus, a series of molecules was synthesized through the Biginelli reaction and their in vitro antiproliferative activity was evaluated in different human cell lines. Then, a quantitative structure-activity relationship (QSAR) analysis was performed using Bayesian regularized artificial neural networks to model the relationships between in silico molecular descriptors and the observed antiproliferative activity of molecules across the tested cell lines. Interestingly, among the compounds prepared, the molecules containing chloro atoms in their structure demonstrated a relevant potency and a selective antiproliferative activity against a novel hepatic cancer cell line (HepaRG) without exhibiting noticeable cytotoxicity in normal dermal cells (NHDF). However, in prostatic (LNCaP), colon (Caco-2) and breast (T47D and MCF-7) cancer cell lines generally the compounds did not exhibit relevant cytoxicity. A statistically valid QSAR model was obtained (internal validation Q(2) - 0.663, RMSECV - 0.071, 10-fold cross-validation procedure, and external validation R-pred(2) = 0.740, RMSE = 0.077), which allowed the analysis of the involved relationships between molecular descriptors and the reliable prediction of the antiproliferative activity for hypothetical related compounds in the studied cell lines. Moreover, flow cytometry analysis showed that in HepaRG and MCF-7 cell lines, compound 16 did not decrease cell viability but, interestingly, led to an accumulation of cells in the G(0)/G(1) phase of the cell cycle. Therefore, chlorinated 3,4-dihydropyrimidin-2-(1H)-ones may be considered promising compounds for further optimization as new antitumor agents.

Books by Mariana Matias

Mitochondrial Dysfunction and Nanotherapeutics, 2021

Melanoma is a complex and highly aggressive skin tumor with increasing incidence worldwide. In th... more Melanoma is a complex and highly aggressive skin tumor with increasing incidence worldwide. In this chapter, this malignant cancer is addressed, gathering information about epidemiology, mitochondrial role in the disease, clinical presentation, and therapeutic management. In the search for novel and more effective therapies against melanoma, pharmacologically active natural products have been explored, with several drugs reaching the market. In vitro and in vivo studies of natural compounds with potential antimelanoma activity are highlighted. Despite their promising potential, some of them can display unfavorable physicochemical and pharmacokinetic features that compromise their clinic translation. Over the last years, there have been advances in nanotechnology applied to cancer treatment that have overcome many of these limitations, providing versatile and effective tools for the successful in vivo delivery of natural molecules, namely lipid-based, polymeric, and metallic nanosystems. These nanocarriers allow not only the modulation of pharmacokinetic and pharmacodynamic profiles of the compounds, but also the increase of their stability and circulation time, resulting in greater therapeutic efficacy and less toxicity. Overall, this chapter focuses on nanoformulated natural-based compounds as an alternative therapeutic approach against melanoma, describing the most representative works from 2008 to 2020.

Cytochrome P450 (CYP450) system is a superfamily of hemecontaining monooxygenase enzymes and repr... more Cytochrome P450 (CYP450) system is a superfamily of hemecontaining monooxygenase enzymes and represents one of the most extensively studied enzymatic systems worldwide. The high interest on CYP450 enzymes reflects not only its importance in the metabolic detoxication of drugs and other xenobiotics from the body, but also its

Pharmaceutics

Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, ... more Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, affecting about 50 million people worldwide. Pharmacological therapy has been, and is likely to remain, the main treatment approach for this disease. Although a large number of new antiseizure drugs (ASDs) has been introduced into the market in the last few years, many patients suffer from uncontrolled seizures, demanding the development of more effective therapies. Nanomedicines have emerged as a promising approach to deliver drugs to the brain, potentiating their therapeutic index. Moreover, nanomedicine has applied the knowledge of nanoscience, not only in disease treatment but also in prevention and diagnosis. In the current review, the general features and therapeutic management of epilepsy will be addressed, as well as the main barriers to overcome to obtain better antiseizure therapies. Furthermore, the role of nanomedicines as a valuable tool to selectively deliver drugs will be ...

Applied Sciences , 2022

C-Ring oxidized estrone acetate derivatives as antiproliferative agents were prepared and tested ... more C-Ring oxidized estrone acetate derivatives as antiproliferative agents were prepared and tested against five cancer cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry assays to evaluate cell viability and modifications in cell cycle phases and molecular docking research against estrogen receptor α, steroid sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 were performed. 9α-Hydroxy,11β-nitrooxyestrone acetate was the most cytotoxic molecule against hormone-dependent cancer cells. Furthermore, flow cytometry experiments revealed that this 9α-hydroxy,11β-nitrooxy derivative markedly reduced HepaRG cells viability (~92%) after 24 h of treatment. However, 9α-hydroxyestrone acetate led to selective inhibition of HepaRG cells growth, inducing a G0/G1 cycle arrest, and did not originate a proliferation effect on T47-D cancer cells. Docking studies estimated a generally lower affinity of these compounds to estrogen receptor α than predicted for estrone and 17β-estradiol. Therefore, this structural modification can be of interest to develop new anticancer estrane derivatives devoid of estrogenic action.

European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences , 2017

The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, bu... more The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood-brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM. The in vitro results suggested that 82% of the test compounds have good intestinal permeability (Papp>1.1×10(-6)cm/s), and 66% of these are also expected to exhibit good permeability through blood-brain barrier (Papp>2.0×10(-6)cm/s); these findings are consistent with a high transport rate by passive transcellular pathway. In both PAMPA models, thiourea derivatives presented higher Papp values than the respective urea analogues, which were further corroborated by in silico predictions. The in vitro results also suggested a low extent of plasma protein binding for all compounds (Papp<1.0×10(-5)cm/s), and these findings were also supported by in silico data (unbound fraction ranging from 0.13 to 0.59). In addition, although approximately half of the compounds did not modulate P-gp at the tested concentrations (10 and 50μM), nine of them presented a trend to induce P-gp and particularly the chlorinated compounds exhibited a marked P-gp inhibition at 50μM. Furthermore, the in silico predictions suggested that half of the compounds have hepatotoxic potential. Overall, within this group of compounds the thiourea derivatives containing an unsubstituted or a monosubstituted (NO2, CH3, OCH3) phenyl ring attached to the position 4 of the dihydropyrimidine ring represented the most promising structures and should be considered in the subsequent studies of the development of new structurally related drug candidates.

European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences , 2017

Although significant advances are occurring in epilepsy research, about 30% of epileptic patients... more Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests. The results of preliminary pharmacological screening after intraperitoneal injection in mice revealed that twenty-four compounds showed protection in half or more of the animals tested in the MES seizure model, being nine of them active at the lowest dose tested (30 mg/kg). Structurally, the most promising compounds (both urea and thiourea derivatives) presented smaller lateral chains and unsubstituted or para-substituted phenyl ring with a methyl group. Compounds 4, 5 and 11 also protected against MES-induced seizures in 50–75% of rats after oral administration at 30 mg/kg. Moreover, the minimal motor and/or neurological impairment evaluated through the rotarod assay showed that around 52% of the compounds presented lower toxicity than the antiepileptic drugs lamotrigine, carbamazepine and phenytoin. In addition, the most active compounds did not show notable cytotoxicity in in vitro experiments conducted in several cell lines (relative cell proliferation higher than 50% at 30 μM), which can be relevant due to the fact that the toxicity is a common problem of the available antiepileptic drugs. Furthermore, additional computational studies indicated that all compounds respected the Lipinski's rule of five, which, together with the data of efficacy and toxicity, make them attractive compounds to be developed in the future as potential anticonvulsant agents.

Mini Reviews in Medicinal Chemistry , 2016

Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing... more Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides, such as enkephalins, deltorphin and endomorphin, have been developed and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control. In addition, as potential antiepileptic drugs, a lot of compounds targeting primarily the GABAergic pathways have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity. Moreover, hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing antioxidant hybrid compounds which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2016

Background: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in ... more Background: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in folk medicine. Due to the claimed anticonvulsant properties of G. elata, it is expected that this herb continues to be a target of research, aiming to deepen the available knowledge on its biological activity and safety. Purpose: The current review aims to discuss the most recent advances on the elucidation of the phytochemical composition and anticonvulsant potential of G. elata. Methods: Available literature was reviewed from PubMed, ISI Web of Knowledge and Science Direct, using combinations of the following keywords: Gastrodia elata, tianma, epilepsy, anticonvulsant and pharmacokinetics. Abstracts and full texts were evaluated for their clarity and scientific merit. Results: G. elata rhizome, as well as specific phenolic compounds isolated from this herb, have demonstrated anticonvulsant potential in a variety of in vitro and in vivo models. The pharmacological mechanisms potentially involved in the anticonvulsant activity have been extensively studied, being similar to the known mechanisms claimed for the available antiepileptic drugs. In addition, the pharmacokinetics of the main bioactive component of G. elata (gastrodin) has also been studied. Conclusion: Due to its recognised therapeutic properties, G. elata has gained an increasing interest within the scientific community and, therefore, new medicinal preparations containing G. elata rhizome itself or its bioactive components are expected to be developed in the coming years. Moreover, specific phytochemical constituents isolated from G. elata may also be considered to integrate programs of discovery and development of new anticonvulsant drug candidates.

Molecules, 2021

The interest in the introduction of the oxime group in molecules aiming to improve their biologic... more The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.

Drug Delivery and Translational Research, 2021

Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major... more Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major cause of cancer-associated deaths. Surgical resection is considered the standard therapeutic choice for CC in early stages. However, in latter stages of the disease, adjuvant chemotherapy is essential for an appropriate management of this pathology. Metal-based complexes displaying cytotoxic properties towards tumor cells emerge as potential chemotherapeutic options. One metallodrug, oxaliplatin, was already approved for clinical use, playing an important role in the treatment of CC patients. Unfortunately, most of the newly designed metal-based complexes exhibit lack of selectivity against cancer cells, low solubility and permeability, high dose-limiting toxicity, and emergence of resistances. Nanodelivery systems enable the incorporation of metallodrugs at adequate payloads, solving the above-referred drawbacks. Moreover, drug delivery systems, depending on their physicochemical properties, are able to release the incorporated material preferentially at affected tissues/organs, enhancing the therapeutic activity in vivo, with concomitant fewer side effects. In this review, the general features and therapeutic management of CC will be addressed, with a special focus on preclinical or clinical studies using metal-based compounds. Furthermore, the use of different nanodelivery systems will also be described as tools to potentiate the therapeutic index of metallodrugs for the management of CC.

Natural Product Research , 2022

10β-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotec... more 10β-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotective activity. However, the cytotoxic properties of this quinol are barely studied. Thus, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF). Additionally, an in vitro estrogenicity assay and a cell viability analysis together with in silico molecular docking studies were carried out in order to understand the potential mechanism of cytotoxicity. Computational predictions of its pharmacokinetic and toxicity properties were also performed. Surprisingly, HEDD displayed marked cytotoxic activity, particularly against hormone-dependent cancer cells and the flow cytometry analysis revealed that HEDD markedly reduced the viability of hepatic cancer cells. Molecular docking studies suggested a high affinity towards the estrogen receptor α and 17β-hydroxysteroid dehydrogenase type 1. Moreover, it was predicted that HEDD may have good oral bioavailability and a low maximum tolerated dose in humans.

Cells, 2021

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resista... more Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

Journal of Pharmacy and Pharmaceutical Sciences, 2018

During the discovery and development of new drugs, compounds with low aqueous solubility pose spe... more During the discovery and development of new drugs, compounds with low aqueous solubility pose special challenges in their pharmacological evaluation and, therefore, the selection of appropriate vehicles to administer the compounds of interest is determinant for the quality of the results generated during the in vivo non-clinical studies. This work aimed to evaluate the motor deficit (as a surrogate of neurotoxicity) of several administration/delivery vehicles through the rotarod performance test. Methods-Trained male CD-1 mice were intraperitoneally administered with the following vehicles: dimethyl sulfoxide (DMSO), aqueous sodium chloride (NaCl) 0.9%, aqueous carboxymethylcellulose (CMC) 0.5%, polyethylene glycol (PEG)-400, propylene glycol (PG), and solutions of these vehicles containing 5% and 10% DMSO. Results-It was observed that the aqueous vehicles (NaCl 0.9% and CMC 0.5%) did not affect the performance of the animals on the rod. On the other hand, a vehicle consisting solely of DMSO led to significant motor impairment and only a small improvement was recorded over time. Additionally, a strong neuromotor toxicity was observed in the early evaluation points of the experiment using vehicles constituted by PG and PEG-400 or by mixtures of PG/DMSO (5% and 10%) and PEG-400/DMSO (5% and 10%). Conclusion-This study provides useful data about the neurotoxicity inherent to several vehicles frequently used in non-clinical pharmaco-toxicological assays, aiming to draw especial attention to the need of a careful selection of drug vehicles in order to avoid the impact of such confounding variables on the accuracy of the results and in decision-making processes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Comptes Rendus Chimie , 2020

A series of D9,11-estrone derivatives with A- and D-ring modifications has been synthesized and e... more A series of D9,11-estrone derivatives with A- and D-ring modifications has been synthesized and evaluated as antiproliferative agents. The cytotoxicity was assessed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and a cell cycle distribution analysis was performed by flow cytometry. Some compounds exhibited relevant cytotoxicity, particularly D9,11-estrone, which was the most active against HepaRG cells (IC50 = 6.67 uM). Besides the relevance of the double bond in the C-ring, the presence of a 16E-benzylidene group increased the antiproliferative effect on MCF-7 and T47-D cells. Moreover, the introduction of iodine in positions 2 and 4 of estrone seemed to induce a selective cytotoxicity for HepaRG cells. Flow cytometry experiments evidenced a 34% reduction of HepaRG cell viability after treatment with D9,11-estrone and a cell cycle arrest at the phase. Estrogenic activity was also observed for this compound at 0.1 uM in T47-D cells, and molecular docking studies estimated a marked interaction between this compound and the estrogen receptor alfa.

Nanomaterials, 2019

Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. T... more Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. The current treatment options involve surgery, radiotherapy, targeted therapy, immunotherapy and the use of chemotherapeutic agents. Although the last approach is the most used, the high toxicity and the lack of efficacy in advanced stages of the disease have demanded the search for novel bioactive molecules and/or efficient drug delivery systems. The current review aims to discuss the most recent advances on the elucidation of potential targets for melanoma treatment, such as aquaporin-3 and tyrosinase. In addition, the role of nanotechnology as a valuable strategy to effectively deliver selective drugs is emphasized, either incorporating/encapsulating synthetic molecules or natural-derived compounds in lipid-based nanosystems such as liposomes. Nanoformulated compounds have been explored for their improved anticancer activity against melanoma and promising results have been obtained. Indeed, they displayed improved physicochemical properties and higher accumulation in tumoral tissues, which potentiated the efficacy of the compounds in pre-clinical experiments. Overall, these experiments opened new doors for the discovery and development of more effective drug formulations for melanoma treatment.

Arabian Journal of Chemistry, 2019

A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1-22) was synthesized through the Biginelli reac... more A series of 3,4-dihydropyrimidin-2-(1H)-thiones (1-22) was synthesized through the Biginelli reaction in order to find novel anticancer drug candidates based on the structure of monastrol. The antiproliferative activity of the compounds was screened in several cell lines and the chlorinated compounds expressed considerable cytotoxicity in hepatic and/or colon and MCF-7 breast cancer cell lines. Within these, compound 11 was the most potent and showed strong antiproliferative effects on HepaRG cells (IC50 = 0.75 μM). Using cell proliferation data, a quantitative structure-activity relationship (QSAR) analysis was performed employing Bayesian regularized artificial neural networks to relate in silico calculated molecular descriptors and bioactivity of the compounds across the tested cell lines. A statistical valid QSAR model was obtained, which allows the prediction of the relative cell proliferation for hypothetical analogous compounds in the studied cell lines. Additionally, cell cycle distribution analysis showed that another potent chlorinated molecule, compound 15, caused accumulation of cells in G0/G1 phase of the cell cycle in HepaRG and MCF-7 cells, which suggests a distinct mechanism of action relatively to monastrol. Overall, chlorinated monastrol analogues showed potent cytotoxic activity in cancer cells and deserve further investigation to ascertain their potential as candidate anticancer agents.

RSC Advances, 2016

The search for novel anticancer agents with higher selectivity and lower toxicity remains a prior... more The search for novel anticancer agents with higher selectivity and lower toxicity remains a priority. This work aimed to design more potent and selective anticancer molecules among the class of 3,4-dihydropyrimidin-2-(1H)-ones. Thus, a series of molecules was synthesized through the Biginelli reaction and their in vitro antiproliferative activity was evaluated in different human cell lines. Then, a quantitative structure-activity relationship (QSAR) analysis was performed using Bayesian regularized artificial neural networks to model the relationships between in silico molecular descriptors and the observed antiproliferative activity of molecules across the tested cell lines. Interestingly, among the compounds prepared, the molecules containing chloro atoms in their structure demonstrated a relevant potency and a selective antiproliferative activity against a novel hepatic cancer cell line (HepaRG) without exhibiting noticeable cytotoxicity in normal dermal cells (NHDF). However, in prostatic (LNCaP), colon (Caco-2) and breast (T47D and MCF-7) cancer cell lines generally the compounds did not exhibit relevant cytoxicity. A statistically valid QSAR model was obtained (internal validation Q(2) - 0.663, RMSECV - 0.071, 10-fold cross-validation procedure, and external validation R-pred(2) = 0.740, RMSE = 0.077), which allowed the analysis of the involved relationships between molecular descriptors and the reliable prediction of the antiproliferative activity for hypothetical related compounds in the studied cell lines. Moreover, flow cytometry analysis showed that in HepaRG and MCF-7 cell lines, compound 16 did not decrease cell viability but, interestingly, led to an accumulation of cells in the G(0)/G(1) phase of the cell cycle. Therefore, chlorinated 3,4-dihydropyrimidin-2-(1H)-ones may be considered promising compounds for further optimization as new antitumor agents.

Mitochondrial Dysfunction and Nanotherapeutics, 2021

Melanoma is a complex and highly aggressive skin tumor with increasing incidence worldwide. In th... more Melanoma is a complex and highly aggressive skin tumor with increasing incidence worldwide. In this chapter, this malignant cancer is addressed, gathering information about epidemiology, mitochondrial role in the disease, clinical presentation, and therapeutic management. In the search for novel and more effective therapies against melanoma, pharmacologically active natural products have been explored, with several drugs reaching the market. In vitro and in vivo studies of natural compounds with potential antimelanoma activity are highlighted. Despite their promising potential, some of them can display unfavorable physicochemical and pharmacokinetic features that compromise their clinic translation. Over the last years, there have been advances in nanotechnology applied to cancer treatment that have overcome many of these limitations, providing versatile and effective tools for the successful in vivo delivery of natural molecules, namely lipid-based, polymeric, and metallic nanosystems. These nanocarriers allow not only the modulation of pharmacokinetic and pharmacodynamic profiles of the compounds, but also the increase of their stability and circulation time, resulting in greater therapeutic efficacy and less toxicity. Overall, this chapter focuses on nanoformulated natural-based compounds as an alternative therapeutic approach against melanoma, describing the most representative works from 2008 to 2020.

Cytochrome P450 (CYP450) system is a superfamily of hemecontaining monooxygenase enzymes and repr... more Cytochrome P450 (CYP450) system is a superfamily of hemecontaining monooxygenase enzymes and represents one of the most extensively studied enzymatic systems worldwide. The high interest on CYP450 enzymes reflects not only its importance in the metabolic detoxication of drugs and other xenobiotics from the body, but also its