An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells.

Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that PAs are effective in inhibiting E2F1 TF activity which results in a temporal reduction in BC-CML cell number. We envisage that PAs could be used in the future to map genes under E2F1 control in CML LSCs.

Organic Semiconductor Laser Platform for the Detection of DNA by AgNP Plasmonic Enhancement.

Organic semiconductor lasers are a sensitive biosensing platform that respond to specific biomolecule binding events. So far, such biosensors have utilized protein-based interactions for surface functionalization but a nucleic acid-based strategy would considerably widen their utility as a general biodiagnostic platform. This manuscript reports two important advances for DNA-based sensing using an organic semiconductor (OS) distributed feedback (DFB) laser. First, the immobilization of alkyne-tagged 12/18-mer oligodeoxyribonucleotide (ODN) probes by Cu-catalyzed azide alkyne cycloaddition (CuAAC) or "click-chemistry" onto an 80 nm thick OS laser film modified with an azide-presenting polyelectrolyte monolayer is presented. Second, sequence-selective binding to these immobilized probes with complementary ODN-functionalized silver nanoparticles, is detected. As binding occurs, the nanoparticles increase the optical losses of the laser mode through plasmonic scattering and absorption, and this causes a rise in the threshold pump energy required for laser action that is proportional to the analyte concentration. By monitoring this threshold, detection of the complementary ODN target down to 11.5 pM is achieved. This complementary binding on the laser surface is independently confirmed through surface-enhanced Raman spectroscopy (SERS).

Oxidative ß-C-H sulfonylation of cyclic amines.

A transition metal-free strategy for the dehydrogenative ß-sulfonylation of tertiary cyclic amines is described. N-Iodosuccinimide facilitates regioselective oxidative sulfonylation at C-H bonds positioned ß to the nitrogen atom of tertiary amines, installing enaminyl sulfone functionality in cyclic systems. Mild reaction conditions, broad functional group tolerance and a wide substrate scope are demonstrated. The nucleophilic character of the enaminyl sulfone is harnessed, demonstrating potential application for scaffold diversification.

Distributed feedback laser for biosensing applications.

We present an organic semiconductor distributed feedback laser biosensor and demonstrate its sensing capabilities. Optimization of the gain layer thickness to maximize the response to refractive index changes and bulk sensing results are shown. Desthiobiotin-avidin sensing assay results are also presented and the potential to perform multiple, repeated sensing measurements is demonstrated.