Antiproliferative Organic Salts Derived from Betulinic Acid: Disclosure of an Ionic Liquid Selective Against Lung and Liver Cancer Cells

Abstract

In the last few years, we have been witnessing an increasing interest in ionic liquids (ILs) and organic salts, given their potential applications in biological and pharmaceutical sciences. We report the synthesis and in vitro evaluation of novel organic salts combining betulinate, known for its anticancer properties, with antimalarial drugs, primaquine, chloroquine, and mepacrine, and also with the trihexyltetradecylphosphonium ([P 6,6,6,14 ]) cation. The salts were screened for their in vitro activity against tumor lines HepG2 (liver), MG63 (osteosarcoma), T47D (breast), A459 (lung), and RKO (colon), and also on normal human fibroblasts. All betulinates prepared displayed antiproliferative properties, with the trihexyltetradecylphosphonium betulinate standing out for its higher selectivity. This unprecedented disclosure of a betulinic acid (BA)-derived IL with selective antitumor activity constitutes a relevant first step toward development of novel anticancer therapies based on BA-derived IL. (1) Ferraz, R.; Branco, L. C.; Marrucho, I. M.; Araujo, J. M. M.; Rebelo, L. P. N.; da Ponte, M. N.; Prudencio, C.; Noronha, J. P.; Petrovski, Z. Development of novel ionic liquids based on ampicillin. MedChemComm 2012, 3, 494−497. (2) Ferraz, R.; Branco, L. C.; Prudencio, C.; Noronha, J. P.; Petrovski, Z. Ionic Liquids as Active Pharmaceutical Ingredients. ChemMedChem 2011, 6, 975−985. (3) Ferraz, R.; Costa-Rodrigues, J.; Fernandes, M. H.; Santos, M. M.; Marrucho, I. M.; Rebelo, L. P. N.; Prudencio, C.; Noronha, J. P.; Petrovski, Z.; Branco, L. C. Antitumor Activity of Ionic Liquids Based on Ampicillin.

Mechanisms of action of ionic liquids on living cells: the state of the art

“… Modulation of three relevant intracellular signaling pathways, i.e., MEK, NF-kB, and JNK, by the novel betulinic acid (BA)–derived IL [P 6,6,6,14 ][BA] has been observed in HFF-1 (fibroblast), HepG2, T47D, and A459 cell lines. More specifically, the addition of this IL downregulates NF-kB and upregulates JNK in HFF-1 cells, and upregulate NF-kB in HepG2 and T47D cells (Silva et al 2019 ). Formation of vesicles in the cytoplasm of HeLa cells after incubation in [C 2 mim][BF 4 ] has also been observed (Wang et al 2007 ).…”

“…In this context, it has been shown, for example, that tri- n -butyl- n -hexadecyl-phosphonium bromide—a phosphonium-based IL with a halogen anion and balanced lengths of C 4 and C 16 alkyl chains—is approximately 100 times more toxic against HeLa cells than several ammonium-based ILs, but it remains inactive against human chronic myelogenous leukemia K562 cells; complementarily, triphenyl-alkyl-phosphonium iodides, with shorter C 1 and C 5 alkyl chains, resulted to be inactive against HeLa cells, but very active against K562 cells (Bachowska et al 2012 ). More recently, (i) a novel betulinic acid–derived IL, i.e., [P 6,6,6,14 ][BA], has shown a specific cytotoxicity against human hepatocellular carcinoma HepG2 and human lung carcinoma A459 tumor cell lines (Silva et al 2019 ), and (ii) a new imidazolium IL with a triphenylphosphonium substituent, applied intravesically to mouse, has selectively killed bladder cancer cells, leaving adjacent healthy cells unaffected (Stromyer et al 2020 ). This selective ability of ILs together with their extreme flexibility in design makes them potential candidates against cancers.…”

Recycling Old Antibiotics with Ionic Liquids

“…ILs were first used as solvents and reagents in a wide range of pharmaceutical processes, and as reaction media in synthetic processes for new and known drugs [ 24 , 25 ]. Currently, ILs are used to form active pharmaceutical ingredients (APIs), taking advantage of their tunable chemical and biological activities, and are also used as part of distinct drug delivery systems for drugs with reduced bioavailability [ 31 , 33 , 34 , 35 , 36 ].…”

Synthesis and Biological Evaluation of Amphotericin B Formulations Based on Organic Salts and Ionic Liquids against Leishmania infantum

“…In this approach, it is possible to take advantage of cation/anion fine-tuning to design compounds with improved physicochemical properties. Therefore, combining counterions with active pharmaceutical ingredients [ 36 , 37 , 38 ] can be relevant for solving solubility, membrane permeability and polymorphism, among other issues [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. In this context, McCrary [ 46 ], Jameson [ 47 ] and their collaborators demonstrated that ionic liquid can be designed to modulate the hydro- and lipophilicity of AmBH, allowing this drug to surpass its solubility and aggregation problems.…”