X-ray crystallographic, FT-IR and NMR studies as well as anticancer and antibacterial activity of the salt formed between ionophore antibiotic Lasalocid acid and amines
Highlights
► Ionophore antibiotic complexes with aromatic and aliphatic amines were obtained. ► Antimicrobial tests demonstrated activity of all compounds studied against Gram-positive bacteria. ► Lasalocid acid and its complexes can be recognized as potential anticancer drug candidates. ► A pseudo-cyclic structure was found to be strictly requested for cytotoxic activities.
Introduction
Natural products have proven to be the most reliable single source of new and effective anticancer agents. Nearly 60% of anticancer and anti-infective agents that are commercially available or in the late stages of clinical trials originate from natural products [1]. Available literature data suggest that the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still topical [2], [3]. Thus, in the field of anticancer drugs, in the time range from the 1940s to date, over 70% of the agents are other than synthetic, with almost 50% actually being either natural products or directly derived from them [4].
Lasalocid acid is a representative of naturally occurring polyether ionophore antibiotics [5], [6]. Ionophores are lipophilic chelating agents that transport cations across lipid bilayer membranes, such as the plasma and subcellular membranes of cells. This unregulated membrane transports of various ions leads to mitochondrial injury and cell swelling, vacuolisation, and finally death [5], [6], [7]. To date, over 120 polyether ionophore structures have been characterized [8]. Ionophore antibiotics show a broad spectrum of bioactivity ranging from antibacterial, antifungal, antiparasitic, antiviral, and recently discovered anti-tumour cell cytotoxicity [9]. The discovery of strong anticancer properties of one of them – salinomycin has received much attention in recent years [10], [11], [12], [13], [14], [15]. It has been shown that salinomycin is 100 times more effective against breast cancer stem-like cells than Taxol (paclitaxel), a commonly chemo-therapeutic drug used against breast cancer [15]. After discovery of the anticancer properties of salinomycin, which has been so far the top candidate for a chemotherapeutic agent among the ionophore antibiotics, other ionophore antibiotics have been more thoroughly explored [14]. It has been also demonstrated that several candidates for chemotherapeutic drugs can be found among other naturally occurring ionophore antibiotics such as monensin A, inostamycin and nigericin [9], [16], [17], [18], [19], [20].
Lasalocid acid (Scheme 1), isolated from Streptomyces lasaliensis, is able to form pseudomacrocyclic complexes with monovalent and divalent cations and to transport these cations across cell membranes [21]. It is commercially used as a coccidiostat for poultry and as growth promoter for ruminants [22].
In previous publications, we have shown that Lasalocid acid forms complexes with allylamine [23] and tetramethylguanidine [24]. The first complex shows higher antibacterial activity than pure Lasalocid and the second complex has antibacterial activity comparable to that of Lasalocid. As an extension of these studies we synthesized and investigated two new hydrogen-bonded complexes of Lasalocid acid (LAS) with aromatic amine (phenylamine, PhA) and aliphatic amine (butylamine, BuA) by X-ray and FT-IR, and NMR spectroscopy. We determined the antimicrobial and cytotoxic activity of the Lasalocid complexes for the first time and compared them to the respective activity of uncomplexed Lasalocid.
Section snippets
General
Lasalocid sodium salt was extracted from Avatec. Phenylamine (PhA) and n-butylamine (BuA) and solvents were obtained from Sigma–Aldrich or Fluka and used without any further purification.
Preparation of Lasalocid–Phenylamine (LAS–PhA) and Lasalocid–Butylamine (LAS–BuA) complexes
Lasalocid sodium salt (1.0 g) was dissolved in dichloromethane (150 ml) and stirred vigorously with a layer of diluted aqueous sulphuric acid (pH = 1.5) (100 ml). The organic layer containing Lasalocid acid (LAS) was washed three times with distilled water. Subsequently dichloromethane was evaporated under reduced
Crystal structure of the Lasalocid–Phenylamine (LAS–PhA) and Lasalocid–Butylamine (LAS–BuA) complexes
The crystals of Lasalocid–Phenylamine (LAS–PhA) and Lasalocid–Butylamine (LAS–BuA) complexes are isostructural. Both complexes crystallise in the same space group and the crystals have very similar unit-cell dimensions (Table 1). The unit-cell dimension a is longer by about 0.5 Å in LAS–PhA, but parameter c is more than 1 Å longer in LAS–BuA, and the unit-cell volumes of both compounds differ in only 5 Å3. It is characteristic that LAS anions assume very similar pseudo-cyclic conformations, with
Conclusions
Two new complexes of ionophore antibiotic Lasalocid acid (LAS) and amines such as phenylamine (PhA) and butylamine (BuA) have been synthesised and their molecular structures have been fully characterized using crystallographic and spectroscopic methods.
In the solid state both complexes of Lasalocid acid are completely deprotonated and the amine groups are protonated. The structures of the complexes are stabilized by the intra- and intermolecular hydrogen bonds formed between the Lasalocid anion
Acknowledgments
Financial support from budget funds for science in years 2012-2013 – Grant ”Iuventus Plus” of the Polish Ministry of Science and Higher Education-No. 0179/IP3/2011/71, is gratefully acknowledged by Adam Huczyński.
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Cited by (14)
Salts or complexes? Factors affecting the type of binding of biogenic organic amines by carboxyl derivatives of 1,1′-dinaphthylmethanes and calix[4]resorcinarenes
2022, TetrahedronCitation Excerpt :The IR spectra of 6а-е, 7а-е showed neither bands for the С=О and О-Н bonds of the starting acids in the 1700-1750 cm−1 and 3300-3600 cm−1 ranges (Table 1) nor doublet bands for the primary NH2 groups of amines 5 in the 3200-3300 cm−1 range (Table S1). The presence of two bands at 1650-1550 cm−1 and 1400-1300 cm−1, similar in intensity, for the symmetric and asymmetric modes of the carboxylate group, in combination with low-intensity bands at 3000-2900 cm−1 and 2100–2300 cm1 and doublet bands in the 1600-1400 cm−1 range (Table S2, Fig. 4a) for the stretching and bending modes of alkylammonium groups attested to complete proton transfer from the carboxyl to amino group [3,6,27]. The protonation of amine molecules with the carboxyl groups of dinaphthylmethanes was also confirmed by 1Н and 13С NMR spectra [27–30], particularly, in the 1Н NMR spectra of 6а-е, 7а-е, the signals of the amine methylene groups were shifted downfield (∼Δ +0.2 ppm), while the signals of the methylene groups bound to the carboxyl group were shifted upfield (∼Δ −0.4 ppm) (Table 2, Fig. 5).
Spectroscopic and structural studies of the first complex formed between salinomycin and organic amine
2017, Journal of Molecular StructureCitation Excerpt :The ionophores can be divided into two groups: those that form complexes only with monovalent cations and those that form complexes with both mono- and divalent cations [4]. Moreover, since 2009 lasalocid acid (LAS) which is one of the ionophores has been known to be able to form complexes with amines and N-organic bases [5–9]. It has been reported that the complex of LAS with allylamine exhibits higher antimicrobial activity than pure LAS, including the activity against hospital strains of Staphylococcus aureus.
Spectroscopic studies of the equilibrium between complexes of lasalocid acid with propargylamine and metal cations
2015, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Recently we have discovered that LAS is able to form stable complexes with N-bases such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) [26], 1,1,3,3-tetramethylguanidine (TMG) [27] and with amines such as allylamine [28], phenylamine and butylamine [29], benzylamine and ammonia [30]. In previous studies we have shown that the complex of LAS with allylamine has a higher antibacterial activity than pure LAS [28] and also that LAS and its complexes with phenylamine and butylamine are relatively strong cytotoxic agents towards cancer cell lines [29]. It is interesting to note that the cytotoxic activity of LAS and its complexes with amines against human cancer cell lines is higher than that of cisplatin – a standard anticancer drug [29].
Spectroscopic, crystallographic and theoretical studies of lasalocid complex with ammonia and benzylamine
2014, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Recently we have discovered that LASH is able to form stable complexes with N-bases such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) [31], 1,1,3,3-tetramethylguanidine (TMG) [32] and several amines such as allylamine [33], phenylamine and butylamine [34]. In previous studies we have shown that the complex of LASH with allylamine has higher antibacterial activity than pure LASH [33] and also that LASH and its complexes with phenylamine and butylamine are relatively strong cytotoxic agents towards cancer cell lines [34]. It is interesting to note that the cytostatic activity of LASH and its complexes with amines against human cancer cell lines is higher than that of cisplatin – a standard anticancer drug [34].
One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic - Lasalocid acid
2013, Bioorganic and Medicinal Chemistry Letters