Ramos-Inza, S. (Sandra)
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- Design and synthesis of new selenoderivatives with biomedical applications(Universidad de Navarra, 2023-01-13) Ramos-Inza, S. (Sandra); Sanmartin-Grijalba, C. (Carmen); Plano-Amatriain, D. (Daniel)The purpose of this Ph.D. project is the development of novel therapeutic agents incorporating the selenium (Se) atom into the structure of small molecules, thus expanding further knowledge about the design and molecular biology of Se-containing drugs. Se is an essential trace element that exerts multiple and complex effects on human health. This element is crucial for human well-being largely due to its involvement in several physiological functions such as protection against oxidative stress or immune response through its incorporation into selenoproteins. Additionally, Se supplementation and adequate maintenance levels of this micronutrient in the organism have been generally related to the prevention of certain pathologies such as cancer, diabetes, neurological disorders, and infections, among others. Accordingly, a plethora of natural and synthetic Se-containing compounds have been recently studied and explored for their therapeutic potential in the treatment of cancer, leishmaniasis, and other diseases. In this context, we designed four series of compounds in which Se was included in a variety of chemical entities, including acylselenourea, selenocyanate, diselenide, and selenide. Different organic nuclei, ferrocene, and NSAIDs as parent molecules that are suitable to be chemically modified by the incorporation of Se into their structures were also considered in our design. Thus, a total of eighty-three novel selenoderivatives were synthesized and purified. Additionally, their preliminary assessment as therapeutic agents were studied in both in vitro and in vivo assays. The results compiled in this Ph.D. project confirm our initial hypothesis of designing selenoderivatives that may confer biomedical properties and provide new strategies and insights for further developing new small molecules containing Se with therapeutic activity. Our results also reinforce the importance of the chemical form of this chalcogen atom in the structure of the organic scaffold, since it is directly linked to the metabolism process and therefore the biological effect of the resulting selenoderivative. The combination of Se entities with other relevant structural features including the incorporation of biologically active frameworks led to the discovery of potent anticancer or even multitarget drugs with additional antileishmanial and antibacterial activities. This Ph.D. memory is expected to provide a basis for future drug development and stimulate further research of new Se-containing compounds with biomedical applications.
- Metal-based compounds containing selenium: An appealing approach towards novel therapeutic drugs with anticancer and antimicrobial effects(Elsevier, 2022) Ramos-Inza, S. (Sandra); Sanmartin-Grijalba, C. (Carmen); Plano-Amatriain, D. (Daniel)In recent years, both metal-based complexes and selenium-containing compounds have been widely explored for their therapeutic properties due to their roles in biological processes and modulation of diverse molecular tar- gets. However, despite their growing interest, there is no review to date that covers the potential use of the combination of these entities to design new therapeutic derivatives. This review highlights the latest achieve- ments in this particular field, with a focus on compounds with anticancer and/or antimicrobial properties. With this aim, the formation of coordination compounds including several metals bearing selenium either with direct interaction with the metal center or as part of the organic ligand elsewhere is covered. Besides, coordination compounds with a Se(IV) center have been assessed. The biological properties of several selenium-containing organometallic complexes have also been discussed, including metallocenes, half-sandwich complexes, and compounds with N-heterocyclic carbenes, CO, and π-ligands, and other σ-bonded entities. The information compiled in this review may be helpful to design and develop novel, more potent, and safer metal-based com- pounds for the treatment of several pathologies.
- Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents(2020) Aydillo-Miguel, C. (Carlos); Ramos-Inza, S. (Sandra); Sanmartin-Grijalba, C. (Carmen); Encío, I. (Ignacio); Plano-Amatriain, D. (Daniel); Talavera-Rodríguez, I. (Irene); Ruberte, A.C. (Ana Carolina)Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents.
- 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, S. (Sandra); Sanmartin-Grijalba, C. (Carmen); Encío, I. (Ignacio); Raza, A. (Asif); Plano-Amatriain, D. (Daniel); Sharma, A.K. (Arun K.)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.
- Thermal characterization, polymorphism, and stability evaluation of Se-NSAID derivatives with potent anticancer activity(Springer, 2023) Ramos-Inza, S. (Sandra); Sirera-Bejarano, R. (Rafael); Sanmartin-Grijalba, C. (Carmen); Encío, I. (Ignacio); Font, M. (María); Plano-Amatriain, D. (Daniel); Almagro, E. (Eneko); Lizarraga, E. (Elena)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 crystal- line 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.