A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

Abstract

This review summarizes part of the author's research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host-guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

Keywords: RNA recognition; RNase mimic; catenanes; intercalation; macrocycles; multi-target drug discovery.

Figure 1

Photographs of Howard E. Zimmerman (July 5, 1926–February 12, 2012) (left) and Jane Zimmerman (née Kirschenheiter) (December 24, 1928–January 21, 1975) (center) as young adults, and the author (right) giving a Breslow group meeting presentation in graduate school (Havemeyer Hall, Columbia University).

Figure 2

(a) Schematic double helix fully saturated with intercalator (in purple) according to the neighbor exclusion principle (NEP). (b) Bisintercalator with spermine linker. (c,d) Bisintercalator with long linker spanning two base-pairs and short linker preferring mono-intercalation to obey NEP. (e) Whitlock’s “rigid” molecular tweezer.

Figure 3

Bismethidium molecular tweezer 3 proposed as a graduate student at Columbia University, which was quite close in structure to 4, synthesized and studied at Illinois. Chemically bonded stationary phase 5 used for HPLC assay of nitrated aromatics and for quantitative enthalpy determinations.

Figure 4

Adenine 8 recognition by carboxylic acid containing tweezer 9 and a component analysis showing “complex additivity” of binding energies.

Figure 5

The first determination of the cost of freezing single bond rotations in a host–guest complex.

Figure 6

Glycouril-based molecular clip 16 and 17 developed by Nolte, an example of Harmata’s chiral Kagan-ether tweezer 18, two of Klärner’s water-soluble tweezers (19 and 20), and pyrene tweezer 21 studied by Colquhoun.

Figure 7

Macrocyclic diacridines and dinaphthalene and the intercalation complexes they may form with one chain in each groove.

Figure 8

(a) Hairpin structure of CUG^exp seen in (CUG)₁₂. (b) U–U or T–T mismatches with no inter-strand hydrogen bonds, hypothetically forming base-triplet with 2,4,6-triamino-1,3,5-triazine. (c) Aromatic recognition unit tethered to intercalator in stacked and unstacked conformation. (d) Ligand 27, an inhibitor of MBNL1N sequestration.

Figure 9

(a) CTG trinucleotide repeat expansion in DMPK gene produces expanded transcripts, one which CUG^exp sequesters splicing regulator MBNL1. Three modes of disease intervention: binding to CTG^exp to inhibit transcription, binding to CUG^exp to inhibit MBNL1 binding, and RNase-like cleavage of CUG^exp. (b) Ligands 28–32.