Discovering novel 7-azaindole-based series as potent AXL kinase inhibitors.

AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL.

Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors.

Efforts were made to improve a series of potent dual ABL/SRC inhibitors based on a 7-azaindole core with the aim of developing compounds that demonstrate a wider activity on selected oncogenic kinases. Multi-targeted kinase inhibitors (MTKIs) were then derived, focusing on kinases involved in both angiogenesis and tumorigenesis processes. Antiproliferative activity studies using different cellular models led to the discovery of a lead candidate (6z) that combined both antiangiogenic and antitumoral effects. The activity of 6z was assessed against a panel of kinases and cell lines including solid cancers and leukemia cell models to explore its potential therapeutic applications. With its potency and selectivity for oncogenic kinases, 6z was revealed to be a focused MTKI that should have a bright future in fighting a wide range of cancers.

Recent progress in the design, study, and development of c-Jun N-terminal kinase inhibitors as anticancer agents.

The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future.

Indium-promoted diastereoselective addition of fluorinated haloallylic derivatives to imines.

We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio. A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the products.

Addition of electrophilic radicals to 2-benzyloxyglycals: synthesis and functionalization of fluorinated α-C-glycosides and derivatives.

A new method for the synthesis of fluorinated α-C-glycosides is described. The reactions between highly electrophilic radicals (fluorinated or unfluorinated) and a 2-benzyloxyglucal or galactal provide 2-keto-D-arabino- or 2-keto-D-lyxo-hexopyranosides through an addition/fragmentation process. Sodium borohydride mediated or Meerwein-Ponndorf-Verley (MPV) reduction of these compounds provides α-C-glycosides that feature appropriate anchoring groups for further synthetic elaboration. The presence of CF2 CO2 iPr or CF2 Br groups at the pseudo-anomeric position allows efficient reduction/olefination or Br/Li-exchange/nucleophilic-addition sequences. These transformations open the way for the synthesis of fluorinated C-glycosidic analogues of glycoconjugates.