np6b01006_si_001.pdf (4.95 MB)
Antineoplastic Agents. 603. Quinstatins: Exceptional Cancer Cell Growth Inhibitors
journal contribution
posted on 2017-02-17, 00:00 authored by George R. Pettit, Noeleen Melody, Jean-Charles ChapuisDiscovery of the exceptionally powerful
anticancer drug dolastatin 10 (1), contained in the sea
hare Dolabella auricularia, opened a new frontier
needed for improving human cancer treatment. Subsequently, major advances
have been achieved based on results of structurally modifying this
unusual natural peptide while maintaining the remarkable anticancer
activity necessary for preparation of successful monoclonal antibody
drug conjugates (ADC). Among the first several hundred SAR products
based on dolastatin 10 our group synthesized and termed auristatins
was auristatin E (2a). An anticancer activity-equivalent,
desmethylaurisatin E (2b), linked to a CD30 monoclonal
antibody is the very successful anticancer drug Adcetris, now approved
for use in 65 countries. In the present investigation, we discovered
a new subset of auristatins designated quinstatins derived from dolastatin
10 by replacing the C-terminal Doe unit with a carefully designed
quinoline, which led to low or subnanomolar levels of cancer cell
growth inhibition required for construction of chemically unique ADC
drugs. The synthesis of quinstatins 2–8 is presented along
with their cancer cell line biological data.