Review Article Macrocyclic Assembly: a Dive Into the Pecking Order and Applied Aspects of Multitalented Metallomacrocycles
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Hindawi Publishing Corporation International Journal of Inorganic Chemistry Volume 2014, Article ID 509151, 30 pages http://dx.doi.org/10.1155/2014/509151 Review Article Macrocyclic Assembly: A Dive into the Pecking Order and Applied Aspects of Multitalented Metallomacrocycles Ashu Chaudhary and Ekta Rawat Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India Correspondence should be addressed to Ashu Chaudhary; [email protected] Received 20 August 2014; Accepted 12 November 2014; Published 18 December 2014 Academic Editor: Stephen Ralph Copyright © 2014 A. Chaudhary and E. Rawat. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To aid in knowledge of macrocyclic complexes and biomedical scientists, we are presenting here a review article with compilation of work done so far along in relation to macrocyclic ligands and their metal complexes. The metal ion chemistry of macrocyclic ligands has now become a major subdivision of coordination chemistry. This overview focuses on developments in design, synthesis, and self-assembly of metal-based architectures and ligands related to macrocyclic chemistry. 1. Introduction and Scope organization which was absent in the linear precursor [6]. Since the birth of macrocycles as early as 1936 [7], the field Macrocycles occupy a unique segment of chemical space. In only began to blossom in early 1960s with the pioneering the past decade, their chemical diversity expanded signifi- work of Thompson and Busch [8]. In such a large subject, cantly, supported by advances in bioinformatics and synthetic this paper can focus only on certain aspects of macrocyclic methodology. As a consequence, this structural type has now chemistry. been successfully tested on most biological target classes. Medicinalchemistshavelongusedmacrocyclizationasa The goal of this paper is to put into perspective the current tool in drug discovery. A classic illustration of this technique applications and opportunities associated with macrocycles was the discovery of potent cyclic peptide somatostatin mim- [1]. Macrocycles are defined herein as molecules containing ics three decades ago [9, 10]. The method of cyclization since at least one large ring composed of nine or more atoms. then developed into a general paradigm in peptidomimetic Macrocycles have several features that make them interesting drug design that has been widely used in the discovery of in efforts to tackle “difficult” targets with extended binding biologically active compounds for studying the cell. These sites [2]. Because of their size and complexity, they can macrocycles represent a new class of structures for further engage targets through numerous and spatially distributed development and for future application in high-throughput binding interactions, thereby increasing both binding affinity screening against a variety of biological targets [11]. Recogni- and selectivity. Furthermore, cyclization provides a degree tion of the importance of complexes containing macrocyclic of structural preorganization that may reduce the entropy ligands has led to a considerable effort being invested in cost of receptor binding compared to linear analogues [3, 4]. developing reliable inexpensive synthetic routes for these Asignificantnumberofmacrocyclicdrugsarecurrentlyon compounds. These macrocycles which contain varying com- the market, predominantly of natural product origin with binations of aza (N), oxa (O) phospha (P), and sulfa (S) ligat- complex structures [5]. This paper is dedicated to explore the ing atoms can be tailored to accommodate specific metal ions field of macrocycles and to highlight salient features of their by the fine-tuning of the ligand design features, such as the versatile chemistry. Cyclization of a linear molecule into a macrocyclic hole size, nature of the ligand donors, donor set, macrocyclicringconstitutesasignificantchangeinmolecular donor array, ligand conjugation, ligand substitution, number shape. This transformation restricts the degrees of confor- and sizes of the chelate rings, ligand flexibility, and nature mational freedom of the molecule and imposes structural of the ligand backbone. A large amount of data has been 2 International Journal of Inorganic Chemistry published on macrocyclic ligands containing only nitrogen, be the first fully characterised examples of discrete f-block only sulphur, or both as donor atoms, namely, tetraaza [12], complexes which can bind sulphur dioxide. Encapsulation thiadiaza [13], thiatriaza [14], dithiadiaza [15, 16], or dithiatri- occurs with gaseous SO2 at room temperature and the aza [17]. However, there is scarce information on thiatetraaza coordination process was analysed using DFT calculations. compounds. In fact, only one thiatetraaza macrocycle, 1- The uranium(III) complex of the related hexadentate chelator thia-4,7,11,14-tetraazacyclohexadecane, was studied [18]. The (Table 1, Compound 2b) can reduce CO2 to CO and CO3 different types of macrocyclic ligands are particularly excit- using KC8 as a reductant to engage the catalytic cycle. ing because of the importance in generating new areas of Nickel(II) and copper(II) complexes of bis-triaza derivatives fundamental chemistry and many opportunities of applied induce B- to Z-DNA transition by the formation of a chemistry. The majority of macrocycles represent creative and macrochelate compound between the dinuclear complexes focused efforts to design molecules which will have particular and the DNA strand, properties which do not occur with uses. the analogous mononuclear triazacyclododecane derivative. The significance of macrocyclic compounds extends from Studies of copper(II) tacn derivatives (Table 1,Compound2c) largenumberoflifecomposingandnaturallyoccurring with a pendant guanidine group show increased rates of DNA complexes with enormous biological functions to vast num- cleavage compared with those of the parent tacn complex. bers of synthetically made ones for diverse biological and Functionalisation of technetium(VII) tacn complex (Table 1, nonbiological functions [19]. These compounds have been Compound 2d) through a (3+2)-cycloaddition reaction of explored for their antibacterial [20], fungicidal [21], anti- the technetium-oxide compound has been performed to convulsant [22], and catalytic [23]activities.Theavailable form M–O–R bonds. This opens up possibilities to form literature has also evidenced about their antioxidant [24]and dual functional BFCs when combined with macrocycle N- anti-HIV activities [25]. These are also used as MRI contrast functionalization. Trisphosphinic acid NOTA derivatives agents [26]. The thermodynamic and kinetic inertness of (Table 1, Compound 2e) have been prepared and their com- transition metal complexes of polyazamacrocyclic ligands plexation properties with gallium(III) explored. Replacement have significant industrial application [27]. of carboxylic acid arms with phosphinic arms increased The family of complexes with macrocyclic ligands has selectivity for binding and forms complexes more efficiently. remained a focus of scientific attention for many decades Iron(II) complexes (Table 1,Compound2f)convertfrom [28]. The chemistry of macrocyclic complexes provide a lowspintohighspinuponadditionofdithioniteandthe huge area of research ranging over many areas of chemistry spin change operates in an aqueous solution altering from andbiochemistry.Thisreviewcompilesadvancesinthe adiamagneticsolutiontoaparamagneticonewiththe synthesis and application of macrocyclic ligands and their associated change in longitudinal relaxation of the water molecules that can be observed by MRI experiments. metal complexes that comprise a linkage between chemistry [12] and biological sciences. A series of mono- and di- aneN3 ligands (Table 1, Compound 3a, 3b and 3c) which contain different sub- stituents on the coordinating backbone, different linkers 2. Aza Macrocycles between two [12]aneN3 units, and different N-methylation on the [12]aneN3 units have been synthesized and fully Important chemical, biological, and medicinal problems characterized by Guo and coworkers. The catalytic activities have been assaulted using azamacrocycles and their metal of their metal complexes on the cleavage of RNA model phos- complexes as useful tools, with significant advances made phate 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP) in a number of these areas. Interest in the smaller tri- varied with the structures of the ligands and metal ions. Click aza macrocycles, ([9]aneN3)(Table 1, Compound 1a) and reactions afforded an efficient method to prepare a series its variations, has also accelerated in recent years. Added of [12]aneN3 ligands. The results clearly indicate that the to the simple polyaza macrocycles has been the effort to structures of the linker between two [12]aneN3 units play achieve functionalized macrocycles in order to expand the very important role in their catalytic synergistic effects31 [ ]. chemistry of these ligands by combining the rigid structural Until recently, the tetraaza macrocycles, such as (cyclam) aspects of the macrocyclic ring with the more flexible and and related ligands with extensive varieties of modifications kinetically labile properties of pendant chains. The design including differing degrees of saturation and ring size, had and development of artificial receptors able to recognise