Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[e]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with E. coli Nitroreductase
摘要:
Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.
Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[e]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with E. coli Nitroreductase
摘要:
Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.
[EN] N-PROTECTED AMINES AND THEIR USE AS PRODRUGS<br/>[FR] AMINES N-PROTEGE ET LEUR UTILISATION EN TANT QUE PROMEDICAMENTS
申请人:CANCER RES CAMPAIGN TECH
公开号:WO2000064864A1
公开(公告)日:2000-11-02
Compounds of formula (I) or (II), wherein X represents H, C1-6 alkyl or C1-6 alkoxy, said alkyl or alkoxy being optionally substituted with one or more groups; a is 0,1,2,3 or 4; Y represents H or C1-6 alkyl; 1, 2 or 3 of the members Z of the 5-membered aromatic ring are independently selected from -O-, -S-, -N= or -NR-, where R is H or C1-6 alkyl optionally substituted with one or more of groups; and E represents a moiety such that EH is an amine; provided that in formula (I) if a = 0 then Y≠H, are provided along with a method of selecting desired protecting groups by measuring the fragmentation rates of compounds of formula (I) or (II) when the nitro group is selected.
Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[<i>e</i>]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with <i>E. </i><i>c</i><i>oli</i> Nitroreductase
作者:Michael P. Hay、Graham J. Atwell、William R. Wilson、Susan M. Pullen、William A. Denny
DOI:10.1021/jm0205191
日期:2003.6.1
Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.