Cinnamalmalononitrile (CM) derivatives have been shown to exhibit a strong photomechanical response in the crystal form. In this paper, the effects of fluorine substitution on the molecular properties, crystal packing, and solid-state photochemical reactivity on this family of photochromes are explored. The addition of fluorines shifts the molecular S 0 − S 1 gap to a higher energy up to 0.4 eV. Fluorination also enables polymorphism in some of the derivatives that effectively controls whether or not they can undergo the [2 + 2] photodimerization. Depending on the substitution pattern, either the head-to-tail (HT, unreactive) or head-to-head (HH, reactive) crystal forms could be obtained. For some derivatives, both polymorphs could be grown depending on the solvent. Theoretical calculations on a subset of these molecules clarify how the fluorination of the CM framework modifies the polymorph landscape and shifts the energetics of the different packing motifs. The CMs appear to support a rich polymorph landscape where HH and HT structures coexist within a few kJ/mol of each other, allowing the simple exchange of an aromatic H atom for an F atom to cause a complete loss of photomechanical activity due to changes in crystal packing. The experimental and computational results highlight how even minor modifications to the molecular structure can alter the resulting crystal structures and photomechanical behavior.
Pseudocyclic β‐trifluorosulfonyloxy vinylbenziodoxolones were prepared starting from hydroxybenziodoxolones and alkynes in the presence of trifluoromethanesulfonic acid. The reaction of these compounds with azide anion leads to β‐azido vinylbenziodoxolones as products of vinylic nucleophilic substitution in which addition‐elimination reactions occur and the double bond configuration is retained. The structures of β‐trifluorosulfonyloxy vinylbenziodoxolone and β‐azido vinylbenziodoxolone were established by single crystal X‐ray diffraction.
Introduction:
Cardiac fibrosis is mediated by the activation of fibroblasts to myofibroblasts, a cell state transition which involves the coordination of expression of hundreds of genes. Previous studies have demonstrated that inhibition of bromodomain and extra-terminal domain (BET) proteins attenuates fibrosis. We recently discovered a novel role of bromodomain-containing protein 4 (BRD4), a BET family member, in maintaining genome folding by stabilizing the cohesin complex (necessary for genome-genome interactions). We hypothesize that BRD4-mediated genome folding is critical for maintaining the enhancer-promoter interactions at genes required for fibroblast activation.
Methods:
A cardiac fibroblast cell line was generated in which a degron epitope tag was appended biallelically to
Brd4
to enable acute BRD4 degradation. Fibroblasts were activated via addition of TGFβ.
Meox1
, a critical transcription factor mediating a broad fibrotic gene program, was used as a model locus to investigate chromatin looping. The proximity between the
Meox1
enhancer and promoter,
Meox1
expression, and protein occupancy at the locus were determined using DNA fluorescence in situ hybridization, RT-qPCR, and chromatin immunoprecipitation (ChIP)-qPCR, respectively.
Results:
The proximity between the
Meox1
enhancer and promoter and
Meox1
expression increased upon TGFβ-induced activation. BRD4 occupancy was enriched at the enhancer of
Meox1
upon activation, and BRD4 depletion reduced
Meox1
expression and the co-localization of the
Meox1
enhancer and promoter. BRD4 physically interacts with the cohesin agonist NIPBL, and we found that co-depletion of BRD4 and a cohesin antagonist normalizes the
Meox1
enhancer and promoter proximity and
Meox1
expression levels. Ongoing studies include genome-wide occupancy studies and expanding our findings to
in vivo
models of cardiac fibrosis.
Conclusions:
Our studies provide a mechanistic understanding of the functional relevance of genome organization during fibroblast activation. These studies will also expand our knowledge on how genome folding regulates cell plasticity and inform therapeutic approaches for targeting pathologic fibrotic remodeling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.