Development of a safe and scalable route towards a tau PET tracer precursor.

A scalable 5-step synthesis of the diazacarbazole derivative 1 used as tau PET tracer precursor is reported. Key features of this synthesis include a Buchwald-Hartwig amination, a Pd catalyzed CH activation and a Suzuki-Miyaura cross-coupling.

Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.

Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1.

A Review on the Anticancer Activity of Carbazole-based Tricyclic Compounds.

Cancers are a huge threat to human life and health. Every year, many people suffer and die from various cancers, and numerous resources have been used to combat cancer. Due to several disadvantages of anticancer agents, such as drug-induced side effects, drug resistance, etc., there are still wide gaps in their ability to conquer cancer. Therefore, there is an urgent need to discover and develop many novel chemotypes to suppress cancer. In this review, we mainly focus on the anticancer potency of two representative sorts of carbazole-based compounds: carboline derivatives and diazacarbazole derivatives. Diazacarbazole derivatives, which have not been fully explored yet, might bring us a new vision and a valuable opportunity for overcoming the enormous hurdle we are now facing in the cancer campaign. We also provide several synthetic approaches for constructing the critical skeletons of the carbazole-based tricyclic compounds.

Double N-arylation reaction of polyhalogenated 4,4'-bipyridines. Expedious synthesis of functionalized 2,7-diazacarbazoles.

Unusual 2,7-diazacarbazoles were prepared in one step from readily available tetra-halogenated 4,4'-bipyridines by using a double N-arylation reaction in the presence of the Pd-XPhos catalyst system. Moderate to good yields were obtained in this site-selective Buchwald-Hartwig double amination. The functionalization of these tricyclic derivatives was performed by using Pd-catalyzed cross-coupling reactions such as the Stille and Suzuki couplings. Two compounds were analyzed by X-ray diffraction and show π-π stacking involving the diazacarbazole moieties and the phenyl rings of functionalized groups.

An insight into DNA binding properties of newly designed cationic δ,δ'­diazacarbazoles: Spectroscopy, AFM imaging and living cells staining studies.

Two cationic δ,δ'­diazacarbazoles, 1­Methyl­5H­pyrrolo[3,2­b:4,5­b']dipyridinium iodide (MPDPI) and 1,5­Dimethyl­5H­pyrrolo[3,2­b:4,5­b']dipyridinium iodide (DPDPI), were devised and synthesized. Through characterizations of the interactions between DNA and the two δ,δ'­diazacarbazoles by various spectroscopy means, the strong interactions between the two compounds and double-strand DNA have been observed and the interaction types and mechanisms were explored. UV-Vis and fluorescent data have shown the big changes of DNA in the presence of either of the two compounds, demonstrating that both of the δ,δ'­diazacarbazoles can bind to DNA tightly, and high ionic strength decreased the intercalative interactions. The UV-Vis and fluorescence of dsDNA in the presence of DPDPI showed more profound changes than those in the presence of MPDPI, due to CH3 (in the structure of DPDPI) taking place of H (in the structure of MPDPI) at the position of 5­NH. And the circular dichroism (CD) spectra of CT-DNA and atomic force microscopy (AFM) results indicated more compacted conformation of DNA in the presence of DPDPI than MPDPI, implying that DPDPI has a more significant effect on DNA conformations than MPDPI. Most interestingly, fluorescence enhancement of cationic δ,δ'­diazacarbazoles occurred in the presence of DNA. With ionic strength increasing, the intercalative interactions between δ,δ'­diazacarbazoles and DNA were weakened, but δ,δ'­diazacarbazoles-DNA complexes showed enhanced fluorescence, which indicated that there are other interactions present at high ionic strength. Furthermore, laser confocal fluorescence microscopy results proved that DPDPI was membrane-permeable and stained living cells.