Natural product-like chemical space: search for chemical dissectors of macromolecular interactions

Macromolecular interactions (i.e. protein\ufffdprotein or DNA/RNA\ufffd protein interactions) play important cellular roles, including cellular communication and programmed cell death. Smallmolecule chemical probes are crucial for dissecting these highly organized interactions, for mapping their function at the molecular level and developing new therapeutics. The lack of ideal chemical probes required to understand macromolecular interactions is the missing link in the next step of dissecting such interactions. Unfortunately, the classical combinatorialchemistry community has not successfully provided the required probes (i.e. natural product inspired chemical probes that are rich in stereochemical and three-dimensional structural diversity) to achieve these goals. The emerging area of diversity-oriented synthesis (DOS) is beginning to provide natural product-like chemical probes that may be useful in this arena.NRC publication: Ye

«Synthesis: Science or Technology?» A Few Comments from an Old-timer

This short commentary adresses some problems associated with the present status and the future of research in organic synthesis. It simply reflects the personal opinion of an author who has been involved with organic synthesis for more than 50 years

Building Skeletally Diverse Architectures on the Indoline Scaffold: The Discovery of a Chemical Probe of Focal Adhesion Kinase Signaling Networks.

NRC publication: Ye

Stereoselective Synthesis of Proline-Derived Dipeptide Scaffolds (ProM-3 and ProM-7) Rigidified in a PPII Helix Conformation

Following a peptide coupling/metathesis-based strategy, the two diastereomeric scaffolds ProM-3 and ProM-7 were stereoselectively synthesized (as 9-fluorenylmethoxycarbonyl derivatives), and their configuration was unambiguously proven by means of X-ray crystallography. The required dehydroisoleucine building blocks were prepared by applying the enantioselective Kazmaier-Claisen rearrangement. The target compounds represent dipeptide analogs rigidified in a PPII helix conformation, which are of interest for the development of new proteomimetics that selectively bind to protein domains specialized in the recognition of ligands adopting a PPII helix secondary structure

Discovery of Indoline-Based, Natural-Product-like Compounds as Probes of Focal Adhesion Kinase Signaling Pathways

With the goal of identifying small molecule modulators of protein 12protein interactions, we developed a solid-phase synthesis method, which was then successfully utilized in a library generation of 164 aminoindoline-derived, natural-product-like compounds. This library and several other related intermediates synthesized during this project were then subjected to different biological assays in search of small molecule modulators of focal adhesion kinase (FAK)-mediated signaling pathways. This study included (i) an in vitro, full length FAK inhibition assay, (ii) a cell proliferation assay, and (iii) a wound healing assay. In FAK inhibition assay, eight library members (5 1212) and three aminoindoline derivatives (13, 14, and 2) were identified as promising candidates. Compounds 13 and 2 inhibited the FAK activity by 25 1245% at 10 \u3bcM. These two lead compounds also showed activity in a wound healing assay. To our knowledge, these aminoindoline-derived small molecules belong to a new family of FAK inhibitors.Peer reviewed: YesNRC publication: Ye