Synthesis and biological evaluation of novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy
Four novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs ( 1a, b and 2a, b) have been synthesized for potential use in carboxypeptidase G2 (CPG2)-based ADEPT therapy. The urea prodrugs ( 1b and 2b) are relatively unstable but the carbamate prodrugs ( 1a and 2a) are both stable in an aqueous environmen...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 16; no. 2; pp. 252 - 256 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
Elsevier Ltd
15.01.2006
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0960-894X 1464-3405 |
| DOI | 10.1016/j.bmcl.2005.10.017 |
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| Abstract | Four novel pyrrolo[2,1-
c][1,4]benzodiazepine prodrugs (
1a,
b and
2a,
b) have been synthesized for potential use in carboxypeptidase G2 (CPG2)-based ADEPT therapy. The urea prodrugs (
1b and
2b) are relatively unstable but the carbamate prodrugs (
1a and
2a) are both stable in an aqueous environment and are good substrates for CPG2.
The design, synthesis and evaluation of four novel pyrrolo[2,1-
c][1,4]benzodiazepine (PBD) prodrugs (
1a,
b and
2a,
b;
Fig. 1) for potential use in carboxypeptidase G2 (CPG2)-based antibody-directed enzyme prodrug therapy (ADEPT) is reported. Although all four prodrugs were shown to be less cytotoxic than the released parent PBDs
3 and
4, the urea prodrugs
1b and
2b were found to be too unstable for use in ADEPT, whereas carbamates
1a and
2a are both stable in an aqueous environment and are good substrates for CPG2. |
|---|---|
| AbstractList | The design, synthesis and evaluation of four novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) prodrugs (1a,b and 2a,b; ) for potential use in carboxypeptidase G2 (CPG2)-based antibody-directed enzyme prodrug therapy (ADEPT) is reported. Although all four prodrugs were shown to be less cytotoxic than the released parent PBDs 3 and 4, the urea prodrugs 1b and 2b were found to be too unstable for use in ADEPT, whereas carbamates 1a and 2a are both stable in an aqueous environment and are good substrates for CPG2. Four novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs ( 1a, b and 2a, b) have been synthesized for potential use in carboxypeptidase G2 (CPG2)-based ADEPT therapy. The urea prodrugs ( 1b and 2b) are relatively unstable but the carbamate prodrugs ( 1a and 2a) are both stable in an aqueous environment and are good substrates for CPG2. The design, synthesis and evaluation of four novel pyrrolo[2,1- c][1,4]benzodiazepine (PBD) prodrugs ( 1a, b and 2a, b; Fig. 1) for potential use in carboxypeptidase G2 (CPG2)-based antibody-directed enzyme prodrug therapy (ADEPT) is reported. Although all four prodrugs were shown to be less cytotoxic than the released parent PBDs 3 and 4, the urea prodrugs 1b and 2b were found to be too unstable for use in ADEPT, whereas carbamates 1a and 2a are both stable in an aqueous environment and are good substrates for CPG2. |
| Author | Begent, Richard H. Spanswick, Victoria J. Hartley, John A. Masterson, Luke A. Thurston, David E. Howard, Philip W. |
| Author_xml | – sequence: 1 givenname: Luke A. surname: Masterson fullname: Masterson, Luke A. organization: CR-UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1 1AX, UK – sequence: 2 givenname: Victoria J. surname: Spanswick fullname: Spanswick, Victoria J. organization: CR-UK Drug-DNA Interactions Research Group, Department of Oncology, University College London, London W1W 7BS, UK – sequence: 3 givenname: John A. surname: Hartley fullname: Hartley, John A. organization: CR-UK Drug-DNA Interactions Research Group, Department of Oncology, University College London, London W1W 7BS, UK – sequence: 4 givenname: Richard H. surname: Begent fullname: Begent, Richard H. organization: CR-UK Targeting and Imaging Group, Department of Oncology, University College London, London W1W 7BS, UK – sequence: 5 givenname: Philip W. surname: Howard fullname: Howard, Philip W. organization: CR-UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1 1AX, UK – sequence: 6 givenname: David E. surname: Thurston fullname: Thurston, David E. email: david.thurston@ulsop.ac.uk organization: CR-UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1 1AX, UK |
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| Cites_doi | 10.1021/jo951631s 10.1158/0008-5472.CAN-03-2942 10.1021/tx00005a002 10.1021/ja00038a089 10.1021/bi952490r 10.1021/jm001064n 10.1016/S0223-5234(01)01253-3 10.1158/0008-5472.CAN-03-2941 10.1021/bi0479813 10.1016/S0960-894X(00)00404-2 10.1021/jm980425k 10.1054/bjoc.2001.1843 10.1039/b205136b 10.1039/c39920001518 10.1093/nar/gki639 10.1093/nar/21.16.3671 |
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| Keywords | PBD Prodrug Pyrrolo[2,1- c][1,4]benzodiazepines ADEPT CPG2 Antineoplastic agent Angular nitrogen heterocycle Lactam Cytotoxicity Organic carbamate Pyrrolo[2,1-c][1,4]benzodiazepines Structure activity relation Targeted drug Ureas Aromatic compound Colon Chemical synthesis Glutamate carboxypeptidase Tumor cell Human Enzyme Gut Antibody directed enzyme prodrug therapy Tricyclic compound Substrate Peptidases Cell line Hydrolases Dimer Metallocarboxypeptidases |
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| References | Gregson, Howard, Hartley, Brooks, Adams, Jenkins, Kelland, Thurston (bib15) 2001; 44 Alley, Hollingshead, Pacula-Cox, Waud, Hartley, Howard, Gregson, Thurston, Sausville (bib16) 2004; 64 Hurley, Reck, Thurston, Langley, Holden, Hertzberg, Hoover, Gallagher, Faucette, Mong, Johnson (bib18) 1988; 1 Clingen, De Silva, McHugh, Ghadessy, Tilby, Thurston, Hartley (bib6) 2005; 33 Cooper, Hagan, Tiberghien, Ademefun, Matthews, Howard, Thurston (bib11) 2002 Niculescu-Duvaz, Friedlos, Niculescu-Duvaz, Davies, Springer (bib3) 1999; 14 Thurston (bib7) 1993 Webley, Francis, Pedley, Sharma, Begent, Hartley, Hochhauser (bib4) 2001; 84 Thurston (bib1) 2005 Sagnou, Howard, Gregson, Eno-Amooquaye, Burke, Thurston (bib17) 2000; 10 Bose, Thompson, Smellie, Berardini, Hartley, Jenkins, Neidle, Thurston (bib13) 1992 Bose, Thompson, Ching, Hartley, Berardini, Jenkins, Neidle, Hurley, Thurston (bib12) 1992; 114 Martin, Ellis, McGurk, Jenkins, Hartley, Waring, Thurston (bib9) 2005; 44 Puvvada, Forrow, Hartley, Stephenson, Gibson, Jenkins, Thurston (bib8) 1997; 36 Niculescu-Duvaz, Niculescu-Duvaz, Friedlos, Martin, Spooner, Davies, Marais, Springer (bib19) 1998; 41 Puvvada, Hartley, Jenkins, Thurston (bib10) 1993; 21 Thurston, Bose, Thompson, Howard, Leoni, Croker, Jenkins, Neidle, Hartley, Hurley (bib14) 1996; 61 Denny (bib2) 2001; 36 Hartley, Spanswick, Brooks, Clingen, McHugh, Hochhauser, Pedley, Kelland, Alley, Schultz, Hollingshead, Schweikart, Tomaszewski, Sausville, Gregson, Howard, Thurston (bib5) 2004; 64 Gregson (10.1016/j.bmcl.2005.10.017_bib15) 2001; 44 Niculescu-Duvaz (10.1016/j.bmcl.2005.10.017_bib3) 1999; 14 Alley (10.1016/j.bmcl.2005.10.017_bib16) 2004; 64 Bose (10.1016/j.bmcl.2005.10.017_bib12) 1992; 114 Thurston (10.1016/j.bmcl.2005.10.017_bib14) 1996; 61 Hurley (10.1016/j.bmcl.2005.10.017_bib18) 1988; 1 Puvvada (10.1016/j.bmcl.2005.10.017_bib10) 1993; 21 Bose (10.1016/j.bmcl.2005.10.017_bib13) 1992 Hartley (10.1016/j.bmcl.2005.10.017_bib5) 2004; 64 Puvvada (10.1016/j.bmcl.2005.10.017_bib8) 1997; 36 Thurston (10.1016/j.bmcl.2005.10.017_bib1) 2005 Niculescu-Duvaz (10.1016/j.bmcl.2005.10.017_bib19) 1998; 41 Sagnou (10.1016/j.bmcl.2005.10.017_bib17) 2000; 10 Denny (10.1016/j.bmcl.2005.10.017_bib2) 2001; 36 Martin (10.1016/j.bmcl.2005.10.017_bib9) 2005; 44 Webley (10.1016/j.bmcl.2005.10.017_bib4) 2001; 84 Thurston (10.1016/j.bmcl.2005.10.017_bib7) 1993 Cooper (10.1016/j.bmcl.2005.10.017_bib11) 2002 Clingen (10.1016/j.bmcl.2005.10.017_bib6) 2005; 33 |
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| Snippet | Four novel pyrrolo[2,1-
c][1,4]benzodiazepine prodrugs (
1a,
b and
2a,
b) have been synthesized for potential use in carboxypeptidase G2 (CPG2)-based ADEPT... The design, synthesis and evaluation of four novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) prodrugs (1a,b and 2a,b; ) for potential use in carboxypeptidase G2... |
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| SubjectTerms | ADEPT Antibodies - chemistry Antibodies - therapeutic use Antigens, Neoplasm - drug effects Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Benzodiazepines - chemical synthesis Benzodiazepines - pharmacology Benzodiazepines - therapeutic use Biological and medical sciences Cell Line, Tumor Cell Survival - drug effects Colonic Neoplasms - drug therapy CPG2 Drug Design Drug Screening Assays, Antitumor gamma-Glutamyl Hydrolase - chemistry gamma-Glutamyl Hydrolase - therapeutic use General aspects Humans Inhibitory Concentration 50 Medical sciences Molecular Structure Nitrogen Mustard Compounds - chemistry Nitrogen Mustard Compounds - pharmacology Nitrogen Mustard Compounds - therapeutic use PBD Pharmacology. Drug treatments Prodrug Prodrugs - chemical synthesis Prodrugs - pharmacology Prodrugs - therapeutic use Pyrroles - chemical synthesis Pyrroles - pharmacology Pyrroles - therapeutic use Pyrrolo[2,1- c][1,4]benzodiazepines Structure-Activity Relationship Time Factors |
| Title | Synthesis and biological evaluation of novel pyrrolo[2,1- c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy |
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