Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity.

SMARCA2 is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the design, synthesis, and biological evaluation of selective SMARCA2 protein degraders developed using the proteolysis targeting chimera (PROTAC) technology. Our efforts have led to the discovery of a series of potent and selective SMARCA2 degraders, exemplified by SMD-3040. SMD-3040 degrades SMARCA2 protein with a low nanomolar DC50 and Dmax > 90% and demonstrates an excellent degradation selectivity for SMARCA2 protein over SMARCA4 protein. It displays potent cell growth inhibitory activity in a panel of SMARCA4-deficient cancer cell lines and has much weaker activity in SMARCA4 wild-type cancer cell lines. SMD-3040 achieves strong tumor growth inhibition in two SMARCA4-deficient xenograft models at well-tolerated dose schedules. Further optimization of SMD-3040 may lead to the discovery of new therapies for the treatment of human cancers with SMARCA4 deficiency.

Hydroesterification and difunctionalization of olefins with N-hydroxyphthalimide esters.

Irradiation of aryl esters of N-hydroxyphthalimides in the presence of unactivated olefins promotes a mild and regioselective hydroesterification. Optimal results are obtained with the aid of fac-Ir(dFppy)3 in CH2Cl2. Terminal and 1,1-disubstituted olefins provide primary esters, and trisubstituted olefins provide secondary esters. The anti-Markovnikov selectivity is consistent with alkyl radical intermediates, which are also indicated by the formation of cyclized products from dienes. Mono-acylated diols are formed from tri- and tetrasubstituted olefins in the presence of water.

Regioselective, Photocatalytic α-Functionalization of Amines.

Photocatalytic α-functionalization of amines provides a mild and atom-economical means to synthesize α-branched amines. Prior examples featured symmetrical or electronically biased substrates. Here we report a controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.

Asymmetric Synthesis of an Advanced Tetracyclic Framework of (+)-Sarain A.

An asymmetric synthetic approach to a tetracyclic framework of the marine-derived alkaloid (+)-sarain A has been developed. The key steps to constructing the congested diazatricycloundecane core include an asymmetric Diels-Alder cycloaddition, an Ireland-Claisen rearrangement, and an intramolecular aziridination/ring-opening sequence.

Asymmetric Total Syntheses of Kopsia Indole Alkaloids.

The asymmetric total syntheses of a group of structurally complex Kopsia alkaloids, (-)-kopsine, (-)-isokopsine, (+)-methyl chanofruticosinate, (-)-fruticosine, and (-)-kopsanone, has been achieved. The key strategies for the construction of the molecular complexity in the targets included an asymmetric Tsuji-Trost rearrangement to set the first quaternary carbon center at C20, an intramolecular cyclopropanation by diazo decomposition to install the second and third quaternary carbon centers at C2 and C7, respectively, and a SmI2 -promoted acyloin condensation to assemble the isokopsine core. A radical decarboxylation of an isokopsine-type intermediate results in a thermodynamic partial rearrangement to give N-decarbomethoxyisokopsine and N-decarbomethoxykopsine, two key intermediates for the syntheses of Kopsia alkaloids with different subtype core structures.