| 摘要 |
A group of cyclic N-acyl O-amino phenol CBI derivatives were synthesized and shown to be pro-drugs, subject to reductive activation by cleavage of a N—O bond, effectively releasing the free drug in functional in vitro cellular assays for cytotoxic activity approaching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Assessment of the in vivo antitumor activity of a representative pro-drug indicates that a contemplated pro-drug approaches the potency and exceeds the efficacy of the free drug itself (CBI-indole2), indicating that the inactive pro-drugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo. |
| 主权项 |
1. A cyclic N-acyl O-amino phenol CBI derivative represented by Formula I:wherein:
R is hydrido or a C1-C6 hydrocarbyl; and R3 is selected from group consisting of radicals represented as follows:wherein:
R4 is selected from group consisting of radicals represented as follows: R5, R6, R7 and R8 are each independently selected from the group of radicals consisting of —H, —OH, —O(C1-C6 hydrocarbyl), C1-C6 hydrocarbyl and halogen; and R9 is selected from the group of radicals consisting of —H, —C(O)O(C1-C6 hydrocarbyl), —C(O)(C1-C6 hydrocarbyl), —C(O)NH2, —C(O)NHNH2, and —C(O)NHNHC(O)O(C1-C6 hydrocarbyl). |
