A Novel, Unusually Efficacious Duocarmycin Carbamate Prodrug That Releases No Residual Byproduct

Abstract

A unique heterocyclic carbamate prodrug of seco-CBI-indole2 that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.

Synthesis, Characterization, and Evaluation of Pluronic-Based β-Cyclodextrin Polyrotaxanes for Mobilization of Accumulated Cholesterol from Niemann-Pick Type C Fibroblasts

“…Hydrolysis of carbamate linkages has been previously reported and, indeed, has been used as a method for designing prodrugs. 47–49 Thus, carbamate cleavage would allow for dethreading of β -CD monomers at high concentration within the LE/LY and subsequent efflux of cholesterol from this compartment.…”

Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents

“…The presence of anomalous spindle fibres due to disrupted microtubule dynamics is a hallmark of cells treated with antimitotic agents. 30 In order to ascertain whether the cell cycle arrest is due to spindle abnormality, HeLa cells were treated with 2 μM concentrations of these conjugates (15a, 15b and 15e) and stained with the tubulin antibody, whereas the control treated cells exhibit an organized network of microtubules. In contrast cells exposed to 15a and 15b showed multipolar spindle fibres, and 15e treated cells exhibited a metaphase arrest (Fig.…”

Antimalarial chemotherapy: Artemisinin-derived dimer carbonates and thiocarbonates

“…This preclinical drug development result suggests that these orally bioavailable dimer carbonates and thiocarbonates act as new chemical entities and possibly as prodrugs 35 of the parent dimer alcohol 12b . Dimer secondary alcohol 12b represents a versatile platform for preparation of other derivatives.…”