A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.
A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) 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.
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
Amanda L
AL
Wolfe
Katharine K
KK
Duncan
Nikhil K
NK
Parelkar
Scott J
SJ
Weir
George A
GA
Vielhauer
Dale L
DL
Boger
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry*; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000737:chemistry; D015195:Drug Design; D000080890:Duocarmycins; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D000970:Antineoplastic Agents; D002219:Carbamates; D003521:Cyclopropanes; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; C058289:duocarmycin A