Due to their potent cytotoxic activity, members of the auristatin family (synthetic analogues of the natural occurring dolastatin 10) have remained a target of significant research, most notably in the context of antibody drug conjugate (ADC) 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 P2 and the P4 subunit in the scientific literature. In this presentation we discuss the introduction of heteroatoms to the P2 and/or P4 side chain; resulting in potent cytotoxic activity seen in vitro.<br/>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.

Synthesis and evaluation of linear and macrocyclic dolastatin 10 analogues containing heteroatoms on the amino acid side chains

2019 Spring National Meeting

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