Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids.

An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacetylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the rhodium catalyst to promote C(sp2)-H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the isoquinolones is very wide and may be extended to the preparation of complex compounds having heterocyclic moieties such as pyridone, furan, thiophene and pyrrole, as well as the corresponding benzo-fused derivatives. The developed procedure is simple, reproducible and does not require inert conditions.

Synthesis of spiroindolenines by intramolecular ipso-iodocyclization of indol ynones.

A high-yielding fast spirocyclization of easily available indol ynones has been developed by applying N-iodosuccinimide. The formation of the desired product occurs in an atom-economical way, under mild conditions, instantly after the addition of the reagent. The expected 1,2-rearrangement was not observed. The procedure represents a metal free spirocyclization of indoles with an opportunity for further functionalizations.

Temperature switchable Brønsted acid-promoted selective syntheses of spiro-indolenines and quinolines.

A high-yielding, temperature switchable divergent approach towards the synthesis of either spiro-indolenines or quinolines is described, starting from easily available indolyl ynones. The application of TFA at rt promotes the dearomatization of the indole, resulting in the formation of the spiro-indolenine, while at higher temperature, rearrangement results in the formation of the quinoline.

Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine†B and C.

An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.