Synthesis of an aminopropyl analog of the experimental anticancer drug tallimustine, and activation of its 4-nitrobenzylcarbamoyl prodrug by nitroreductase and NADH

Lee, Moses; Simpson, Jacob E.; Woo, Shirley; Kaenzig, Crystal; Anlezark, Gill; Eno-Amooquaye, E.; Burke, Philip J.

doi:10.1016/s0960-894x(97)00162-5

Cited by 18 publications

(13 citation statements)

References 21 publications

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“…More recently a novel p -nitro-substituted benzyl carbamate enediyne prodrug activated by nitroreductase NR2 from E. coli in the presence of NADH has been demonstrated by Denny and co-workers 9 to possess in vitro activity and thus of potential utility in the treatment of cancer. A similar strategy using nitroreductase and NADH activation of a Tallmustine prodrug has also been reported . Another very creative use of the BE system for use with anticancer drugs, as exemplified by doxorubicin or daunorubicin, has been pursued by two groups. , In this particular design, an amino group is latentiated by making it part of a benzyl carbamate linker with the para functionality (hydroxy or amino) bound to glucuronic acid or a galactopyranose derivative.…”

Section: Introductionmentioning

confidence: 99%

“…A similar strategy using nitroreductase and NADH activation of a Tallmustine prodrug has also been reported. 10 Another very creative use of the BE system for use with anticancer drugs, as exemplified by doxorubicin or daunorubicin, has been pursued by two groups. 11,12 In this particular design, an amino group is latentiated by making it part of a benzyl carbamate linker with the para functionality (hydroxy or amino) bound to glucuronic acid or a galactopyranose derivative.…”

Section: Introductionmentioning

confidence: 99%

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Drug Delivery Systems Employing 1,4- or 1,6-Elimination: Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

et al. 1999

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A general methodology for synthesizing poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed and constitutes the basis for solubilization of insoluble drugs, extending plasma circulating half-lives and, in the case of anticancer agents, apparent tumor accumulation. Thus, we have successfully designed PEG conjugated specifiers or "triggers" as part of a double-prodrug strategy that relies, first, on enzymatic separation of PEG followed by the classical and rapid 1,4- or 1, 6-benzyl elimination reaction releasing the amine (drug) bound in the form of a carbamate. The prodrug trigger was comprised of ester, carbonate, carbamate, or amide bonds in order to secure predictable rates of hydrolysis. Further refinement of the hydrolysis was accomplished by the introduction of steric hindrance through the use of ortho substituents on the benzyl component of the prodrug. This modification led to longer circulating plasma half-lives of the final tripartate form. The "ortho" effect also had the beneficial effect of directing nucleophilic attack almost exclusively to the activated benzyl 6-position of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this study ultimately identified the type 1 carbamate (34b), with a circulating t(1/2) of 4 h, as the most effective derivative for solid tumor growth inhibition.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Drug Delivery Systems Employing 1,4- or 1,6-Elimination: Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

et al. 1999

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“…Among these hybrid molecules, the compound 196a was 2-6-fold more cytotoxic than the parent compound AHMA. 224 Recently, both our 225,226 and Lown's group 227 have reported the synthesis, biological activity, and DNA binding properties of novel hybrids (197)(198)(199)(200), consisting respectively of one, two, three, or four pyrrole amide units linked to a pyrrolo [2,1-c] [1,4] benzodiazepine 201, through a spacer arm, to study the structure-activity relationship between the length of the oligopyrrolic frame, antiproliferative activity, and sequence specificity. The rationale that led to the synthesis of this series of pyrrolo [2,1-c] [1,4] benzodiazepine-lexitropsin conjugates was to tether the distamycin A frame, which plays the role of pure minor groove binder, to the minor groove alkylating moiety represented by the pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) 201, with the aim to obtain new derivatives which could result in more cytotoxic than the parent compounds.…”

mentioning

confidence: 99%

“…The rationale that led to the synthesis of this series of pyrrolo [2,1-c] [1,4] benzodiazepine-lexitropsin conjugates was to tether the distamycin A frame, which plays the role of pure minor groove binder, to the minor groove alkylating moiety represented by the pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) 201, with the aim to obtain new derivatives which could result in more cytotoxic than the parent compounds. In these new hybrids (197)(198)(199)(200), we conjugated the capability of PBD 201 to covalently bind to GC-rich sequences with that of distamycin's different recognition pattern.…”

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confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

364

222

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DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1-c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames.

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“…4-Nitrobenzyl carbamate prodrugs ( 29a, 30a ) of DNA major groove alkylating pyrrolo[2,1-c]benzodiazepines ( 29b ) [140], and of DNA minor groove alkylating tallimustine mustards ( 30b ) [141] showed differential cytotoxicity towards cells in culture when cotreated with NTR plus cofactor NADH, but studies have not been reported in NTR-transfected cell lines. The enediyne prodrug ( 31a ) showed moderately selective cytotoxicity (135 fold) in the NTR-transfected WiDr human colon carcinoma cell line [142].…”

Section: Prodrugs For Nitroreductase (Ntr)mentioning

confidence: 99%

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

Denny

2003

BioMed Research International

105

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This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy.

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Synthesis of an aminopropyl analog of the experimental anticancer drug tallimustine, and activation of its 4-nitrobenzylcarbamoyl prodrug by nitroreductase and NADH

Cited by 18 publications

References 21 publications

Drug Delivery Systems Employing 1,4- or 1,6-Elimination: Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

Drug Delivery Systems Employing 1,4- or 1,6-Elimination: Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

DNA minor groove binders as potential antitumor and antimicrobial agents

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

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