Person:
Encío Martínez, Ignacio

person.page.identifierURI

https://academica-e.unavarra.es/handle/2454/48954

Last Name

Encío Martínez

First Name

Ignacio

person.page.departamento

Ciencias de la Salud

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IMAB. Research Institute for Multidisciplinary Applied Biology

ORCID

0000-0003-1732-1989

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455

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Now showing 1 - 10 of 14

Open Access
Organoseleno cytostatic derivatives: autophagic cell death with AMPK and JNK activation
(Elsevier Masson SAS, 2019) Garnica, Pablo; Encío Martínez, Ignacio; Plano, Daniel; Palop, Juan Antonio; Sanmartín, Carmen; Ciencias de la Salud; Osasun Zientziak
Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI50 values below 10 μM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.
Open Access
Seleno-warfare against cancer: decoding antitumor activity of novel acylselenoureas and se-acylisoselenoureas
(MDPI, 2024) Angulo-Elizari, Eduardo; Raza, Asif; Encío Martínez, Ignacio; Sharma, Arun K.; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
Currently, cancer remains a global health problem. Despite the existence of several treatments, including chemotherapy, immunotherapy, and radiation therapy, the survival rate for most cancer patients, particularly those with metastasis, remains unsatisfactory. Thus, there is a continuous need to develop novel, effective therapies. In this work, 22 novel molecules containing selenium are reported, including seven Se-acylisoselenoureas synthesized from aliphatic carbodiimides as well as acylselenoureas with the same carbo- and heterocycles and aliphatic amines. After an initial screening at two doses (50 and 10 µM) in MDA-MB-231 (breast), HTB-54 (lung), DU-145 (prostate), and HCT-116 (colon) tumor cell lines, the ten most active compounds were identified. Additionally, these ten hits were also submitted to the DTP program of the NCI to study their cytotoxicity in a panel of 60 cancer cell lines. Compound 4 was identified as the most potent antiproliferative compound. The results obtained showed that compound 4 presented IC50 values lower than 10 µM in the cancer cell lines, although it was not the most selective one. Furthermore, compound 4 was found to inhibit cell growth and cause cell death by inducing apoptosis partially via ROS production. Overall, our results suggest that compound 4 could be a potential chemotherapeutic drug for different types of cancer.
Open Access
Seleno-analogs of scaffolds resembling natural products a novel warhead toward dual compounds
(MDPI, 2023) Astráin-Redín, Nora; Talavera, Irene; Moreno, Esther; Ramírez, María J.; Martínez-Sáez, Nuria; Encío Martínez, Ignacio; Sharma, Arun K.; Sanmartín, Carmen; Plano, Daniel; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Ciencias de la Salud
Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10−6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.
Open Access
New formulation of a methylseleno-aspirin analog with anticancer activity towards colon cancer
(MDPI, 2020) Ruberte, Ana Carolina; González Gaitano, Gustavo; Sharma, Arun K.; Aydillo, Carlos; Encío Martínez, Ignacio; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak
Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, β-and γ-cyclodextrin (CD), a modified β-CD (hydroxypropyl β-CD, HP-β-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with β-and HP-β-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with β-and HP-β-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, β-CD, HP-β-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature.
Open Access
Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: identification of a Se-indomethacin analog as a potential therapeutic for breast cancer
(Elsevier, 2022) Ramos Inza, Sandra; Encío Martínez, Ignacio; Raza, Asif; Sharma, Arun K.; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB
A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid, naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a larger panel of cancer cells and were also submitted to the DTP program of the NCI's panel of 60 cancer cell lines. Compounds 4a and 4d stood out with IC50 values below 10 μM in several cancer cells along with a selectivity index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic drug for breast cancer.
Open Access
A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells
(Wiley, 2017) Díaz, Marta; González, Roncesvalles; Plano, Daniel; Palop, Juan Antonio; Sanmartín, Carmen; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase‐dependent apoptosis and arrest at the G0/G1 phase in acute lymphoblastic leucemia CCRF‐CEM cells. Consistent with this, PARP cleavage; enhanced caspase‐2, ‐3, ‐8 and ‐9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF‐CEM cells retains its transactivating activity. Therefore, increased levels of p21CIP1 and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G2/M cell cycle arrest and caspase‐independent cell death in p53 deficient HTB‐54 lung cancer cells. Autophagy inhibitors 3‐methyladenine, wortmannin and chloroquine inhibited DPDS 6‐induced cell death. Consistent with autophagy, increased LC3‐II and decreased SQSTM1/p62 levels were detected in HTB‐54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho‐p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125‐protected HTB‐54 cells from DPDS 6‐induced cell death indicating that JNK activation is involved in DPDS 6‐induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential.
Open Access
Unveiling a new selenocyanate as a multitarget candidate with anticancer, antileishmanial and antibacterial potential
(MDPI, 2022) Ramos Inza, Sandra; Henriquez-Figuereo, Andreina; Moreno, Esther; Berzosa, Melibea; Encío Martínez, Ignacio; Plano, Daniel; Sanmartín, Carmen; Ciencias de la Salud; Osasun Zientziak
Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel–Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a–b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC50 values below 12 µM, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1–2a displayed potent antileishmanial activity in L. major and L. infantum, with IC50 values below 5 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.
Open Access
First generation of antioxidant precursors for bioisosteric Se-NSAIDs: design, synthesis, and in vitro and in vivo anticancer evaluation
(MDPI, 2023) Ramos Inza, Sandra; Aliaga, César; Encío Martínez, Ignacio; Raza, Asif; Sharma, Arun K.; Aydillo, Carlos; Martínez-Sáez, Nuria; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak
The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC50 < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.
Open Access
Synthesis and pharmacological screening of several aroyl and heteroaroyl selenylacetic acid derivatives as cytotoxic and antiproliferative agents
(MDPI, 2009) Sanmartín, Carmen; Plano, Daniel; Domínguez, Enrique; Font, María; Calvo, Alfonso; Prior, Celia; Encío Martínez, Ignacio; Palop, Juan Antonio; Ciencias de la Salud; Osasun Zientziak
The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH(2)-COOH or Heterar-CO-Se-CH(2)-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with alpha-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3, 5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 mu M. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 mu M. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.
Open Access
Thermal characterization, polymorphism, and stability evaluation of Se-NSAID derivatives with potent anticancer activity
(Springer, 2024) Ramos Inza, Sandra; Almagro, Eneko; Font, María; Encío Martínez, Ignacio; Plano, Daniel; Sanmartín, Carmen; Sirera, Rafael; Lizarraga, Elena; Ciencias de la Salud; Osasun Zientziak
Stability, thermal characterization, and identification of possible polymorphism are relevant in the development of novel therapeutic drugs. In this context, thirty new nonsteroidal anti-inflammatory drug (NSAID) derivatives containing selenium (Se) as selenoesters or diacyl diselenides with demonstrated anticancer activity were thermally characterized in order to establish thermal stability criteria and detect possible polymorphic forms. Compounds were analyzed by a combination of thermogravimetry, differential scanning calorimetry, and X-ray diffraction techniques, and five different calorimetric behaviors were identified. Two compounds based on naproxen (I.3d and I.3e) and an indomethacin-containing derivative (II.2) presented two crystalline forms. The stability under acid, alkaline and oxidative conditions of selected polymorphs was also assessed using high-performance liquid chromatography. In addition, the cytotoxic activity of Se-NSAID crystalline polymorphs was studied in several cancer cell lines in vitro. Remarkably, no significant differences were found among the polymorphic forms tested, thus proving that these compounds are thermally qualified for further drug development.