No abstract

Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration (FDA)-approved ADCs, Adcetris ® and Polivy ®. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups. Our group's main focus is to investigate the structure-activity relationships (SAR) of novel auristatins with the goal of applying these to next generation ADCs. Modifications of the auristatin backbone scaffold have been widely reported in the chemical literature focusing on the terminal subunits: P1 (N-terminus) and P5 (C-terminus). Our approach was to modulate the activity and hydrophilic character through modifications of the central subunits P2-P3-P4 and thorough SAR study on the P5 subunit. Novel hydrophilic auristatins were observed to have greater potency in vitro and displayed enhanced in vivo antitumor activity when conjugated via protease-cleavable linkers and delivered intracellularly. Analysis of ADC aggregation also indicated that novel hydrophilic payloads enabled the synthesis of high-drug-to-antibody ratio (DAR) ADCs that were resistant to aggregation. Modification of the central peptide subunits also resulted in auristatins with potent cytotoxic activity in vitro and these azide-modified auristatins contain a handle for linker attachment from the central portion of the auristatin backbone.

Because of their potent cytotoxic activity, members of the auristatin family (synthetic analogues of the naturally occurring dolastatin 10) have remained a target of significant research, most notably in the context of antibody drug conjugate payloads. Typically, modifications of the backbone scaffold of dolastatin 10 have focused on variations of the N-terminal (P1) and C-terminal (P5) subunits. Scant attention has been paid thus far to the P4 subunit in the scientific literature. In this paper, we introduce an azide functional group at the P4 subunit, resulting in potent cytotoxic activity seen in vitro. Another highly active compound in this study contained azide functional groups in both the P2 and P4 subunits and required dolavaline as the P1 subunit and a phenylalanine as the P5 subunit. Furthermore, these two azide groups served not only as modifiers of cytotoxicity but also as handles for linker attachment or as a tether for use in the synthesis of a macrocyclic analogue.

When life gives you lemons: An efficient and convergent enantioselective total synthesis of (−)‐lemonomycin, which shows potent activity against methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus faecium (VREF), is presented. The key reaction steps are a Hosomi–Sakurai‐type cyclization, a thermodynamically controlled Pictet–Spengler reaction, and a glycosidation reaction with lemonose (see scheme).

No abstract