Browsing by Author "Santos, Miguel M."
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- Alendronic Acid as Ionic Liquid: New Perspective on OsteosarcomaPublication . Teixeira, Sónia; Santos, Miguel M.; Fernandes, Maria H.; Costa-Rodrigues, Joao; Branco, Luís C.Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic techniques and their solubility in water and biological fluids was determined. An evaluation of the toxicity towards human healthy cells and also human breast, lung and bone (osteosarcoma) cell lines was performed. Globally, it was observed that the monoanionic OSILs showed lower toxicity than the corresponding dianionic structures to all cell types. The highest cytotoxic effect was observed in OSILs containing a [C2OHMIM] cation, in particular [C2OHMIM][ALN]. The latter showed an improvement in IC50 values of ca. three orders of magnitude for the lung and bone cancer cell lines as well as fibroblasts in comparison with ALN. The development of OSILs with high cytotoxicity effect towards the tested cancer cell types, and containing an anti-resorbing molecule such as ALN may represent a promising strategy for the development of new pharmacological tools to be used in those pathological conditions.
- Antitumor Activity of Ionic Liquids Based on AmpicillinPublication . Ferraz, Ricardo; Costa-Rodrigues, Joao; Fernandes, Maria H.; Santos, Miguel M.; Marrucho, Isabel M.; Rebelo, Luís Paulo N.; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, Željko; Branco, Luís C.Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API-ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API-ILs showed IC50 values between 5 and 42 nm, activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines—skin (SF) and gingival fibroblasts (GF)—indicates that the majority of these API-ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1-hydroxyethyl-3-methylimidazolium–ampicillin pair ([C2OHMIM][Amp]), making this the most suitable lead API-IL for future studies.
- Etidronate-based organic salts and ionic liquids: In vitro effects on bone metabolismPublication . Teixeira, Sónia; Santos, Miguel M.; Branco, Luís C.; Costa-Rodrigues, JoãoBisphosphonates are a class of drugs widely used for the treatment of several pathologies associated with increased bone resorption. Although displaying low oral bioavailability, these drugs have the ability to accumulate in bone matrix, where the biological effects are exerted. In the present work, four mono- and dianionic Etidronate-based Organic Salts and Ionic Liquids (Eti-OSILs) were developed by combination of this drug with the superbases 1,1,3,3-tetramethylguanidine (TMG) and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) as cations, aiming to improve not only the physicochemical properties of this seminal bisphosphonate, but also its efficacy in the modulation of cellular behavior, particularly on human osteoclasts and osteoblasts. It was observed that some of the developed compounds, in particular the dianionic ones, presented very high water solubility and diminished or absent polymorphism. Also, several of them appeared to be more cytotoxic against human breast and osteosarcoma cancer cell lines while retaining low toxicity to normal cells. Regarding bone cells, a promotion of an anabolic state was observed for all Eti-OSILs, primarily for the dianionic ones, which leads to an inhibition of osteoclastogenesis and an increase in osteoblastogenesis. The observed effects resulted from differential modulation of intracellular signaling pathways by the Eti-OSILs in comparison with Etidronate. Hence, these results pave the way for the development of more efficient and bioavailable ionic formulations of bisphosphonates aiming to effectively modulate bone metabolism, particularly in the case of increased bone resorption.
- A Novel Approach for Bisphosphonates: Ionic Liquids and Organic Salts from Zoledronic AcidPublication . Teixeira, Sónia; Santos, Miguel M.; Ferraz, Ricardo; Prudêncio, Cristina; Fernandes, Maria H.; Costa-Rodrigues, Joao; Branco, Luís C.Novel ionic liquids and organic salts based on mono- or dianionic zoledronate and protonated superbases, choline and n-alkylmethylimidazolium cations, were prepared and characterized by spectroscopic and thermal analyses. Most of the prepared salts display amorphous structures and very high solubility in water and saline solutions, especially the dianionic salts. Among the zoledronate-based ionic compounds, those containing choline [Ch] and methoxyethylmethylimidazolium [C3 OMIM] cations appear to have significant cytotoxicity against human osteosarcoma cells (MG63) and low toxicity toward healthy skin fibroblast cells. Because osteosarcoma is a bone pathology characterized by an increase in bone turnover rate, the results presented herein may be a promising starting point for the development of new ionic pharmaceutical drugs against osteosarcoma.
- Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant BacteriaPublication . Ferraz, Ricardo; Silva, Dário; Dias, Ana Rita; Dias, Vitorino; Santos, Miguel M.; Pinheiro, Luís; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, Željko; Branco, Luís C.The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichiacoli and Staphylococcusaureus strains is reported. Eleven hydrolyzed β-lactam-OSILs were obtained after precipitation in moderate-to-high yields via the neutralization of the basic ammonia buffer of antibiotics with different cation hydroxide salts. The obtained minimum inhibitory concentration (MIC) data of the prepared compounds showed a relative decrease of the inhibitory concentrations (RDIC) in the order of 100 in the case of [C2OHMIM][seco-Pen] against sensitive S. aureus ATCC25923 and, most strikingly, higher than 1000 with [C16Pyr][seco-Amx] against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. These outstanding in vitro results showcase that a straightforward transformation of standard antibiotics into hydrolyzed organic salts can dramatically change the pharmaceutical activity of a drug, including giving rise to potent formulations of antibiotics against deadly bacteria strains.
- Tackling bacterial resistance using antibiotics as ionic liquids and organic saltsPublication . Santos, Miguel M.; Grilo, Inês R.; Ferraz, Ricardo; Madeira, Diogo A.; Soares, Bárbara M.; Inácio, Núria; Pinheiro, Luís; Petrovski, Zeljko; Prudêncio, Cristina; Sobral, Rita G.; Branco, Luís C.Bacterial resistance to current antibiotics has a major impact on worldwide human health, leading to 700K deaths every year. The development of novel antibiotics did not present significant progress, namely regarding clinical trials, over the last years due to low returns. Thus, innovative alternatives must be devised to tackle the continuous rise of antimicrobial resistance. Ionic Liquids and Organic Salts from Active Pharmaceutical Ingredients (API-OSILs) have risen in academia for over 10 years as an efficient formulation for drugs with low bioavailability and permeability, as well as reduction or elimination of polymorphism, thereby potentially enhancing their pharmaceutical efficiency. To the best of our knowledge, our group is the first to perform research on the development of API-OSILs from antibiotics as a way to improve their efficiency. More specifically, we have successfully combined ampicillin, penicillin and amoxicillin as anions with biocompatible organic cations such as choline, alkylpyridiniums and alkylimidazoliums. In this communication, we present our latest developments in the synthesis and physicochemical (DSC) characterization of OSILs from these antibiotics, in addition to in vitro antimicrobial activity data, in particular towards MRSA and multi-resistant E. coli, as well as sensitive strains of gram-positive and gram-negative bacteria.
- Toxicity screening of Diclofenac, Propranolol, Sertraline and Simvastatin using Danio rerio and Paracentrotus lividus embryo bioassaysPublication . Ribeiro, Sílvia; Torres, Tiago; Martins, Rosario; Santos, Miguel M.Early life-stage bioassays have been used as an alternative to short-term adult toxicity tests since they are cost-effective. A single couple can produce hundreds or thousands of embryos and hence can be used as a simple high-throughput approach in toxicity studies. In the present study, zebrafish and sea urchin embryo bioassays were used to test the toxicity of four pharmaceuticals belonging to different therapeutic classes: diclofenac, propranolol, simvastatin and sertraline. Simvastatin was the most toxic tested compound for zebrafish embryo, followed by diclofenac. Sertraline was the most toxic drug to sea urchin embryos, inducing development abnormalities at the ng/L range. Overall, our results highlight the potential of sea urchin embryo bioassay as a promising and sensitive approach for the high-throughput methods to test the toxicity of new chemicals, including pharmaceuticals, and identify several drugs that should go through more detailed toxicity assays.