Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines.

A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engineered rate constants to selectively target tumor tissue with short-lived cytotoxic moieties. EPR based tumor accumulation (half-life ~ 15 h) is dependent upon the ubiquitous abnormal solid tumor capillary morphology and is expected to be independent of individual tumor cell genetic variability that leads to resistance to molecularly targeted agents.

1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119): a cytotoxic prodrug with two stable conformations differing in biological and physical properties.

The anticancer prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively releases a short-lived cytotoxin following enzymatic reduction in hypoxic environments found in solid tumors. KS119, in addition to two enantiomers, has two stable atropisomers (conformers differing in structure owing to hindered bond rotation) that interconvert at 37 °C in aqueous solution by first-order kinetics with t(1/2) values of ∼50 and ∼64 h. The atropisomers differ in physical properties such as partition coefficients that allow their chromatographic separation on non-chiral columns.