The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.
The autoxidative annulation cascade promoted by an α-cyano β-TMS-capped alkynyl cycloalkanone system under catalysis with pyridine in one oxygen atmosphere has proven to be highly viable. On the basis of this newly developed protocol, a variety of highly functionalized bicyclic frameworks can be effectively constructed.
The total synthesis of natural lignans 5′‐methoxyyatein (1), 5′‐methoxyclusin (2), and 4′‐hydroxycubebinone (3), in racemic form, has been achieved by a newly developed strategy, wherein lithium naphthalenide induced decyanation was employed as a key operation to establish the essential trans configuration of the butyrolactone ring.
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