Novel Prodrugs of Alkylating Agents Derived from 2-Fluoro- and 3-Fluorobenzoic Acids for Antibody-Directed Enzyme Prodrug Therapy

Cj, Springer; Niculescu‐Duvaz, Ion; Pedley, RB

doi:10.1021/jm00041a015

Cited by 36 publications

(16 citation statements)

References 10 publications

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“…As the nitrogen mustard prodrugs we have previously synthesised did not contain fluorine, 23 we have prepared two new nitrogen mustards 8 and 18 with a fluorine tag. It must be reminded that some fluorinated nitrogen mustard prodrugs have already been reported by Springer et al, 35 but they widely differ from the prodrugs which are reported in the present study. Indeed, instead of glutamic-containing prodrugs as reported by Springer et al, 35 the prodrugs that constitute the basis of this study are phenol glucuronides.…”

Section: Introductioncontrasting

confidence: 49%

“…It must be reminded that some fluorinated nitrogen mustard prodrugs have already been reported by Springer et al, 35 but they widely differ from the prodrugs which are reported in the present study. Indeed, instead of glutamic-containing prodrugs as reported by Springer et al, 35 the prodrugs that constitute the basis of this study are phenol glucuronides. Compound 8 bears an analogy to Roffler's prodrug 20 in that the drug is directly linked to glucuronic acid.…”

Section: Introductioncontrasting

confidence: 49%

See 1 more Smart Citation

In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Monneret

2002

J. Chem. Soc., Perkin Trans. 1

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Section: Introductioncontrasting

confidence: 49%

Section: Introductioncontrasting

confidence: 49%

In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Monneret

2002

J. Chem. Soc., Perkin Trans. 1

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“…Further work indicated that two prodrugs related to CMDA: 3-fluoro-4-[bis (2-chloroethyl)amino]benzoyl-Lglutamic acid 22 and 3,5-difluoro-4-[bis(2-iodoethyl)amino]benzoyl-L-glutamic acid, 2 23 were superior to CMDA in terms of cytotoxic differential, potency, and the bystander effect in vitro and in vivo in a number of CPG2/GDEPT systems. The reasons for these improvements are unclear.…”

Section: Introductionmentioning

confidence: 99%

Significant Differences in Biological Parameters between Prodrugs Cleavable by Carboxypeptidase G2 That Generate 3,5-Difluoro-phenol and -aniline Nitrogen Mustards in Gene-Directed Enzyme Prodrug Therapy Systems

et al. 2004

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Nine new nitrogen mustard compounds derived from 2,6-difluoro-4-hydroxy- (3a-e) and 2,6-difluoro-4-amino- (4a-d) aniline were synthesized as potential prodrugs. They were designed to be activated to their corresponding 3,5-difluorophenol and -aniline (4)-nitrogen mustards by the enzyme carboxypeptidase G2 (CPG2) in gene-directed enzyme prodrug therapy (GDEPT) models. The compounds were tested for cytotoxicity in the MDA MB-361 breast adenocarcinoma. The cell line was engineered to express stably either CPG2 tethered to the cell surface stCPG2-(Q)3 or beta-galactosidase (beta-Gal) as control. The cytotoxicity differentials were calculated between CPG 2-expressing and -nonexpressing cells and yielded different results for the two series of prodrugs despite their structural similarities. While the phenol compounds are ineffective as prodrugs, their aniline counterparts exhibit outstanding activity in the tumor cell lines expressing CPG2. [3,5-Difluoro-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl-l-glutamic acid gave a differential of >227 in MDA MB361 cells as compared with 19 exhibited by 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-l-glutamic acid, 1a, which has been in clinical trials.

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“…10 since it has no mammalian homologue. 11 This enzyme catalyzes the scission of an amidic, 11,12 urethanic, or ureidic 13,14 bond between an aromatic nucleus and L-glutamic acid.…”

Section: Introductionmentioning

confidence: 99%

Self-Immolative Nitrogen Mustard Prodrugs for Suicide Gene Therapy

Niculescu‐Duvaz

Friedlos

et al. 1998

J. Med. Chem.

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Four new potential self-immolative prodrugs derived from phenol and aniline nitrogen mustards, four model compounds derived from their corresponding fluoroethyl analogues and two new self-immolative linkers were designed and synthesized for use in the suicide gene therapy termed GDEPT (gene-directed enzyme prodrug therapy). The self-immolative prodrugs were designed to be activated by the enzyme carboxypeptidase G2 (CPG2) releasing an active drug by a 1, 6-elimination mechanism via an unstable intermediate. Thus, N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheny l)c arbamoyl]-L-glutamic acid (23), N-[(4-¿[4-(bis¿2-chloroethyl¿amino)phenoxycarbonyloxy]methyl¿pheno xy) carbonyl]-L-glutamic acid (30), N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen oxy)carbonyl]-L-glutamic acid (37), and N-[(4-¿[N-(4-¿bis[2-chloroethyl]amino¿phenyl)carbamoyloxy]methyl¿+ ++phen yl)carbamoyl]-L-glutamic acid (40) were synthesized. They are bifunctional alkylating agents in which the activating effects of the phenolic hydroxyl or amino functions are masked through an oxycarbonyl or a carbamoyl bond to a benzylic spacer which is itself linked to a glutamic acid by an oxycarbonyl or a carbamoyl bond. The corresponding fluoroethyl compounds 25, 32, 42, and 44 were also synthesized. The rationale was to obtain model compounds with greatly reduced alkylating abilities that would be much less reactive with nucleophiles compared to the corresponding chloroethyl derivatives. This enabled studies of these model compounds as substrates for CPG2, without incurring the rapid and complicated decomposition pathways of the chloroethyl derivatives. The prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs by CPG2 for use in GDEPT. The synthesis of the analogous novel parent drugs (21b, 51) is also described. A colorectal cell line was engineered to express CPG2 tethered to the outer cell surface. The phenylenediamine compounds were found to behave as prodrugs, yielding IC50 prodrug/IC50 drug ratios between 20- and 33-fold (for 37 and 40) and differentials of 12-14-fold between CPG2-expressing and control LacZ-expressing clones. The drugs released are up to 70-fold more potent than 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoic acid that results from the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA) which has been used previously for GDEPT. These data demonstrate the viability of this strategy and indicate that self-immolative prodrugs can be synthesized to release potent mustard drugs selectively by cells expressing CPG2 tethered to the cell surface in GDEPT.

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Novel Prodrugs of Alkylating Agents Derived from 2-Fluoro- and 3-Fluorobenzoic Acids for Antibody-Directed Enzyme Prodrug Therapy

Cited by 36 publications

References 10 publications

In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Significant Differences in Biological Parameters between Prodrugs Cleavable by Carboxypeptidase G2 That Generate 3,5-Difluoro-phenol and -aniline Nitrogen Mustards in Gene-Directed Enzyme Prodrug Therapy Systems

Self-Immolative Nitrogen Mustard Prodrugs for Suicide Gene Therapy

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