Systematic synthetic and biophysical development of mixed sequence DNA binding agents

Abstract

It is now well established that, although only about 5% of the human genome codes for protein, most of the DNA has some function, such as synthesis of specific, functional RNAs and/or control of gene expression. These functional sequences open immense possibilities in both biotechnology and therapeutics for the use of cell-permeable, small molecules that can bind mixed-base pair sequences of DNA for regulation of genomic functions. Unfortunately very few types of modules have been designed to recognize mixed DNA sequences and for progress in targeting specific genes, it is essential to have additional classes of compounds. Compounds that can be rationally designed from established modules and which can bind strongly to mixed base pair DNA sequences are especially attractive. Based on extensive experience in design of minor-groove agents for AT recognition, a small library of compounds with two AT specific binding modules, connected through linkers which can recognize the G·C base pairs, were prepared. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that some pyridyl-linked compounds bind with the target sequence with sub-nanomolar KD, with very slow dissociation kinetics and 200 times selectivity over the related sequence without a G·C base pair. Interestingly, a set of compounds with AT module connected by different linkers shows cooperative dimer recognition of related sequences. This type of design approach can be expanded to additional modules for recognition of a wide variety of sequences.

Synthesis and circularly polarized luminescence properties of BINOL-derived bisbenzofuro[2,3-b:3’,2’-e]pyridines (BBZFPys)

“…In general, functionalization of the BINOL hydroxy groups should be performed at temperatures below 80 °C to prevent racemization [40,41]. 6,6'-Di-tert-butyl-1,1'-bi-2-naphthol (1) was treated with 2,6-difluoropyridine using cesium carbonate as base in DMF at 40 °C [42], giving both the enantiomers of 2 in optically pure forms. The remaining fluorine substituents were subsequently replaced by a series of phenols including unsubstituted phenol, p-tert-butylphenol, and m-tert-butylphenol to produce the corresponding unsymmetrically substituted pyridines 3a-c in high yields.…”

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

“…Our goal was to prepare entirely new types of compounds without the amide group that could bind to mixed A⋅T and G⋅C bps containing sequences but would also have varied chemical and structural properties that would allow them to specifically bind to target sequences and effectively target a variety of different cell types. The initial research in the area has produced quite different compounds that are undergoing additional development to increase affinity and selectivity for the target sequence type with a single G⋅C flanked by A⋅T bps . Among them, the N‐MeBI‐thiophene containing compounds were found to be effectively modified to improve their binding affinity and specificity …”

“…The initial research in the area has produced quite different compounds that are undergoing additional development to increase affinity and selectivity for the target sequencet ype with as ingle G·C flanked by A·T bps. [19][20][21] Among them, the N-MeBI-thiophene containing compounds were found to be effectively modified to improve their binding affinity and specificity. [22] Incorporating the N-MeBI thiophene unit into ah eterocyclic cationb ase structure,a si nF igure 1, resulted in DB2429 which can recognize at arget G·C bp in an AT sequence.…”

Synthesis of Nitrogen-containing 4-alkoxybenzaldehyde Analogues

“…Indeed, our research group had spent much time synthesizing Afatinib derivatives to find compounds that show more potency. During the development process of these kinds of new compounds, nitrogen-containing 4-alkoxybenzaldehyde analogues play an important role since they have wide usefulness in the pharmaceutical and chemical fields [5][6][7]. These groups are frequently focused of interest in medicinal chemistry because of their broad spectrum of activities: anticancer, antimicrobial, antiviral, analgesic, anti-inflammatory, antimicrobial, antihistaminic, antiangiogenic etc.…”