Diastereoselective Spirocyclization: Entry to Spirocyclic Diketopiperazines.

We report a novel approach to access spirocyclic compounds containing a diketopiperazine (DKP) motif fused on a pyrrolidine ring. The shared spirocyclic carbon is at the ketone oxidation state, bearing two carbon-nitrogen bonds, one of which is introduced stereoselectively during the cyclization event. The reaction proceeds through an acid-catalyzed cyclization of a pendent chiral aminoamide unit onto a 2,3-dehydroproline amide moiety with up to >98:2 diastereoselectivity. We have demonstrated the generality of this methodology and its applicability to access chemically diverse DKP-containing structures. The extent of stereoinduction and how it varies according to the bulkiness of the substituent on the pendent aminoamide is demonstrated through a diverse substrate set. This methodology gives access to an underexplored spirocyclic diketopiperazine motif that may be useful in identifying new bioactive molecules.

Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells.

Oncology treatment has been revolutionized by the introduction of immune checkpoint inhibitor drugs, which enable 20-40% of patients to generate anti-tumor immune responses. Combination treatment approaches with chemotherapeutic drugs may enable responses in the remaining patient cohorts. In this regard, a handful of drugs are promising due to their ability to induce immunogenic cell death in target cells. However, these agents are systemically delivered and indiscriminately cytotoxic to proliferating cells. By contrast, antibody-drug conjugates can selectively deliver a cytotoxic payload to a tumor, sparing most healthy cells. The ability of antibody-drug conjugates to induce immunogenic cell death in target cells has not yet been determined, although preclinical in vivo studies suggest this possibility. Here, we describe for the first time production of the in vitro hallmarks of immunogenic cell death - ecto-calreticulin and secreted ATP and HMGB1 protein - by cells in response to treatment with antibody-drug conjugates bearing a maytansine payload.

Cu-Click Compatible Triazabutadienes To Expand the Scope of Aryl Diazonium Ion Chemistry.

Triazabutadienes can be used to readily generate reactive aryl diazonium ions under mild, physiologically relevant conditions. These conditions are compatible with a range of functionalities that do not tolerate traditional aryl diazonium ion generation. To increase the utility of this aryl diazonium ion releasing chemistry an alkyne-containing triazabutadiene was synthesized. The copper-catalyzed azide-alkyne cycloaddition ("Cu-click") reaction was utilized to modify the alkyne-containing triazabutadiene and shown to be compatible with the nitrogen-rich triazabutadiene. One of the triazole products was tethered to a fluorophore, thus enabling the direct fluorescent labeling of a model protein.