Chemical Tagging of Bioactive Amides by Cooperative Catalysis: Applications in the Syntheses of Drug Conjugates.

ABSTRACT

We disclose a practical catalytic method for arming bioactive amide-based natural products and other small-molecule drugs with various functional handles for the synthesis of drug conjugates. We demonstrate that a set of readily available Sc-based Lewis acids and N-based Brønsted bases can function cooperatively to deprotonate amide N-H bonds in polyfunctional drug molecules. An aza-Michael reaction between the resulting amidate and α,ß-unsaturated compounds produces an array of drug analogues that are equipped with an alkyne, azide, maleimide, tetrazine, or diazirine moiety under redox and pH-neutral conditions. The utility of this chemical tagging strategy is showcased through the production of drug conjugates by the click reaction between the alkyne-tagged drug derivatives and an azide-containing green fluorescent protein, nanobody, or antibody.