Abstract
The aim of this review is to provide mainly an outlook of the synthesis and characterization of chiral mono- and α-diimines ligands and their Pd(II) complexes carried out in our group in the last few years. Some other issues with simple chiral imines synthesized in our lab are also outlined. The report includes details about their versatile coordination patterns, biological activity in cancer cell lines, and engaging properties in different fields, such as materials science.
Keywords
- chiral imines
- Pd complexes
- solvent-free reactions
- anticancer activity
1. Introduction
The importance of Schiff bases resides in their structural variety as well as their ability to form a wide range of appealing structural arrangements depending of the constituents parent molecules with transition metals by acting as
We have focused our attention on the synthesis of chiral compounds since chirality is almost omnipresent in a broad range of organic molecules in the human body such as proteins, enzymes, amino acids, carbohydrates, and nucleosides. The body acts like a chiral selector metabolizing enantiomers by separate pathways and generating different pharmacological activities. For that reason, the current approach is to target specific molecules by designing more selective drugs, especially in chemotherapy where the distinction between cancerous and normal cells is essential for the success of the treatment and the reduction of the toxicity.
Likewise, the search of more eco-friendly procedures in the synthesis of organic molecules is one of the goals of our research group. Green Chemistry techniques like the use of microwave irradiation and solvent-free reactions display numerous advantages such as shorter reaction times, minimum waste, operational simplicity as well as reduction of thermal degradative byproducts along with cleaner work-up and generally higher yields [9, 10].
On the other hand, the discovery of anticancer activity of the cisplatin was a key event for the introduction of metal-based compounds to medicine, and the interest on these kind of compounds increased significantly in the last decades due to their ability to coordinate ligands in a three-dimensional configuration and bind to specific cell targets. Platinum-based drugs, particularly cisplatin, are widely use in the treatment of different types of cancer, but the toxicity and high resistance that they present limits their use. Therefore, the major challenge for chemists is the design of new drugs with less side effects. Efforts have been made to consider other metal-based complexes with cytotoxic properties, such as palladium complexes. They are known to show structural and thermodynamic analogy in regard to Pt(II) complexes, and display versatile coordination behavior and interesting properties. Palladium complexes of various donor-atom ligands have been found to possess engaging anti-tumor activity, as well as anti-inflammatory, anti-microbial, antiviral and antifungal properties [11, 12].
2. Chiral Pd(II) complexes
The incorporation of optically pure aromatic amines into α-dicarbonylic compounds bearing aromatic rings such as benzil in a 1/1 ratio generating enantiopure α-ketoimines was the first step for our investigations, considering that a flexible X〓C▬C〓N (X = O, N) skeleton could lead to diverse coordination modes [13]. Then, the chiral mono-imine derived from (
On the other hand,
Complex
The complexes
Also, we have reported the synthesis of cyclopalladated compounds. Considering that our previous compounds displayed attractive properties, we decided to vary the substituents, replacing the aromatic rings in the α-dicarbonylic compounds by aliphatic substituents, such as two methyl groups and attaching also two chiral entities, i.e., to prepare α-diimines, as such kind of compounds have also a flexible N〓C▬C〓N skeleton, displaying outstanding electron donor and acceptor properties and can potentially act in a variety of coordination modes. Then, the chiral diimines
Both complexes
Thereafter, we carried out the synthesis of new unsymmetrical α-diimines by replacing one methyl group with a hydrogen atom and enlarging the number of chiral amines. A different method was used with the aim to improve the yields. Then, methylglyoxal and optically active aromatic and alicyclic primary amines were stirred in diethyl ether with Na2SO4 for 24 hours at room temperature leading to the formation of the ligands
Complexes
It seems that the small substituents on the imine N atoms facilitates the orientation toward σ, σ, N, N′ coordination mode, stabilizing the complex through the chelate effect, while the monodentate (σ-N) coordination mode is favored by sterically hindered systems.
The results of the cytotoxic assay showed that Pd complexes with monodentate (σ-N) coordination mode (
As such results were unpromising, we reconsidered the α-dicarbonylic compounds bearing aromatic rings, but this time with heterocyclic entities. By using the method previously used (microwave irradiation in solvent-free conditions), the chiral α-ketoimines
Complexes
The data from the sulforhodamine B assay evidenced that none of the compounds possess cytotoxicity toward K562, however they are able to inhibit cell growth in U251, PC-3, HCT-15 and MCF-7, being
Such results were not particularly impressive (at least a factor of 10 poorer than cisplatin), but they certainly do show variations in activity as well in the other cases.
It must be pointed out that even when the Pd-Schiff Base-complexes displayed cell growth inhibition against different classes of cancer, the IC50 that they have showed are not comparable with cisplatin. In general, Pd(II) complexes are kinetically less stable than those of Pt(II), by losing their structural integrity in biological fluids in a short period of time due to their rapid exchange. More specific studies
On the other hand, considering other alternatives to the flexible X〓C▬C〓N (X = O, N) skeleton, for example as a heterodiene, we have also reported the microwave-assisted Diels-Alder [4+2] cycloaddition reaction of the optically pure α-ketoimines
With the chiral α-diimines
In addition, extending our studies to include some other transition metals, we have reported the preparation of chiral Hg(II) complexes with simpler chiral imines
Solutions of the chiral imines
Likewise, preliminary data have revealed that chiral imines
On the other hand, simpler chiral imines have triggered interest in some other fields, especially in materials science; where by changing the substituents in the chiral moiety can afford morphological, optical and structural changes resulting in photoluminescent properties, which are extremely interesting since the viewpoint of physicists. In this context, we have recently reported a series of halogenated imines (Figure 13) derived from 2-naphtaldehyde and optically pure halogenated amines, under solvent-free conditions. As a result, imines
Likewise, in a series of chiral imines derived from 2-naphtaldehyde but with the halogen atoms in the
3. Conclusion
The chemistry of Schiff bases and their transition metal complexes, especially Pd, is a field that is being noticed not only for their remarkable biological properties but also for their extensive applications in other fields. This area requires further studies to be carried out, and improvements in the permeability and transport are some of the factors to take into account in the design of these metal-based complexes.
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