Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Abstract

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

Keywords: biosensing; clefts; clips; controlled release; drug delivery; imaging; molecular switches; molecular tweezers; responsive systems.

Figure 1

Schematic representation of the molecular tweezers, clefts, clips and switches introduced to describe acyclic synthetic receptors, and their first reported examples.

Figure 2

Examples of synthetic receptors for adenine and guanosine recognition.

Figure 3

Receptors developed by Zimmerman: from molecular tweezers to triaminotriazine ligands for trinucleotide repeat recognition and cleavage. Adapted from [15].

Figure 4

Molecular tweezers developed by Nakatani et al. to detect bulges and mismatches in DNA. Adapted from [33,35,36,37].

Figure 5

Molecular tweezers developed to detect CGG repeat causing hairpins and their pharmaceutical applications. Adapted from [42,46,47].

Figure 6

Phosphate molecular clip and tweezers developed by Klärner and their applications as enzyme inhibitors, illustrated by the alcohol dehydrogenase (ADH), protein aggregation inhibitors illustrated by amyloid β (Aβ) fibril aggregation, protein-protein interaction modulator and antiviral agent. Adapted from [54,55].

Figure 7

Examples of molecular tweezers used for sugar detection. Adapted from [75,78].

Figure 8

Examples of metal-switching tweezers. Adapted from [81,84,85,86].

Figure 9

Examples of lipid switches used for stimulus-responsive drug release. Adapted from [88,104].

Figure 10

Overview of the pharmaceutical applications of molecular tweezers, clefts and clips.