Publications

CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) is a novel synthetic retinoic acid derivative that has been shown to selectively induce apoptosis in human lung cancer cells. This compound, however, is limited in its application due to its low solubility in aqueous solutions. One technique for increasing the solubility and bioavailability of a cytotoxic agent is the formation of inclusion complexes with cyclodextrins. Herein, we report the formation and characterization of a 2:1 complex between β-cyclodextrin (β-CD) and CD437. It is shown that CD437 is a tight binder of β-CD with an overall association constant of 2.6 ± 0.6 × 10⁷ M⁻². In addition, we demonstrate (a) that β-CD-derived complexation enhances the aqueous solubility of CD437, and (b) that a significant increase in the toxicity of CD437 against a human lung adenocarcinoma cell line can be achieved by co-treatment with β-CD.

A convenient approach for the self-assembly of well-defined porphyrin nanowires in water, wherein the individual monomers do not aggregate via π−π interactions, is disclosed. These unidirectional and heteromeric assemblies are instead composed of robust β-CD/adamantane host/guest interactions. A combination of surface microscopies and fluorescence energy transfer experiments were conducted on the nanowires demonstrating their stability and resistance to disassembly.

A novel water-soluble nanorod is discussed, which is prepared via the self-assembly of pristine C₆₀ and a double-sided porphyrin projecting four β-cyclodextrins from each face.

A new stilbene-tethered bis(porphyrin) tweezer has been synthesized that exists as two configurational isomers. UV/Vis, fluorescence, and MALDI-TOF studies have demonstrated that the Z isomer exhibits asignificantly larger affinity towards fullerenes. The photoisomerization of the high-affinity (Z) isomer to the low-affinity (E) configuration is also discussed.

The development of oligonucleotide-linked small molecules for protein recognition is a worthy undertaking with potential applications in drug discovery and diagnostics. Although the ground work for this novel approach to protein recognition is still being laid, a number of promising systems have recently been developed. Herein, we discuss a selection of these systems focusing on the distinct tactics that can be employed for protein binding. Also reported is a new example that underscores the unique versatility of linking aptamers to protein-binding small molecules. In particular, we discuss the development of a chimeric aptamer that in the ‘on’ state can bind and signal the presence of a target protein. Furthermore, we demonstrate that the activity of this sensing supramolecule can be switched ‘off’ on cue.

The naturally occurring nucleic acid bases (nucleobases) adenine, thymine (uracil), guanine, and cytosine are widely appreciated for their ability to stabilize canonical Watson–Crick base-pairing motifs, as well as a number of other well-characterized arrangements, such as Hoogsteen and wobble heterodimers, and a variety of homodimers. In this tutorial review, the use of these kinds of interactions to form synthetic polymeric and oligomeric ensembles is summarized. Particular emphasis will be placed on synthetic analogues of guanine that stabilize the formation of well-defined higher order aggregates, as well as de novo polymeric systems whose properties are modulated by the presence of nucleobase derivatives incorporated within or attached to the chain-defining backbone. In both cases, nucleobase–nucleobase interactions serve to underlie the chemistry, establish the structural morphology, and enable the development of bioinspired, environmentally responsive materials.

Pentaplex oligonucleotides: Oligonucleotide strands containing repeats of isoguanine bases are studied by mass spectrometry and circular dichroism in the presence of various cations. Isoguanine strands tend to form five-stranded structures surrounding central cations (as can be seen with isoguanine bases shown in the figure), which are similar to guanine quadruplexes observed in vivo. With some cations, however, isoguanine quadruplexes were also formed.

A supramolecular assembly containing an isoguanosine pentaplex with both a “protein-binding” face and a “reporter” face has been generated. When phosphocholine is appended to the protein-binding face this supramolecular assembly binds multivalently to the pentameric human C-reactive protein, a biomolecule implicated in inflammation and heart disease.

In this communication, we disclose a generalizable strategy for developing agents with regulable protein-binding ability. In particular, a responsive DNA-small molecule chimera (DC) 1 consisting of two synthetic protein-binding arms and a core oligonucleotide (ODN) domain is discussed. DC 1 can be cycled from a bidentate intramolecular quadruplex form to a monodentate duplex structure, via addition of external ODN stimuli. Importantly, these distinct secondary structures of 1 lead to significantly different protein-binding abilities, with the bidentate conformation showing a 20-fold enhancement (with a 0.8 μM dissociation constant, K_d) in trypsin-binding potency.

Based on binding studies undertaken by electrospray ionization-mass spectrometry, a synthetic pyrrole–inosine nucleoside, 1, capable of forming an extended three-point Hoogsteen-type hydrogen-bonding interaction with guanine, is shown to form specific complexes with two different quadruplex DNA structures [dTG₄T]₄ and d(T₂G₄)₄ as well as guanine-rich duplex DNA. The binding interactions of two other analogs were evaluated in order to unravel the structural features that contribute to specific DNA recognition. The importance of the Hoogsteen interactions was confirmed through the absence of specific binding when the pyrrole NH hydrogen-bonding site was blocked or removed. While 2, with a large blocking group, was not found to interact with virtually any form of DNA, 3, with the pyrrole functionality missing, was found to interact non-specifically with several types of DNA. The specific binding of 1 to guanine-rich DNA emphasizes the necessity of careful ligand design for specific sequence recognition.