Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

David E. Thurston; D. Subhas Bose; Andrew S. Thompson; Philip W. Howard; Alberto Leoni; Stephen J. Croker; Terrence C. Jenkins; Stephen Neidle; John A. Hartley; Laurence H. Hurley

doi:10.1021/jo951631s

Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

David E. Thurston, D. Subhas Bose, Andrew S. Thompson, Philip W. Howard, Alberto Leoni, Stephen J. Croker, Terrence C. Jenkins, Stephen Neidle, John A. Hartley, Laurence H. Hurley

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

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Abstract

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The 'amino thioacetal' cyclization procedure was used to produce the electrophilic DNA-interactive N10-C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.

Original language	English (US)
Pages (from-to)	8141-8147
Number of pages	7
Journal	Journal of Organic Chemistry
Volume	61
Issue number	23
DOIs	https://doi.org/10.1021/jo951631s
State	Published - Nov 15 1996

ASJC Scopus subject areas

Organic Chemistry

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10.1021/jo951631s

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title = "Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents",

abstract = "An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The 'amino thioacetal' cyclization procedure was used to produce the electrophilic DNA-interactive N10-C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.",

author = "Thurston, {David E.} and Bose, {D. Subhas} and Thompson, {Andrew S.} and Howard, {Philip W.} and Alberto Leoni and Croker, {Stephen J.} and Jenkins, {Terrence C.} and Stephen Neidle and Hartley, {John A.} and Hurley, {Laurence H.}",

year = "1996",

month = nov,

day = "15",

doi = "10.1021/jo951631s",

language = "English (US)",

volume = "61",

pages = "8141--8147",

journal = "Journal of Organic Chemistry",

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publisher = "American Chemical Society",

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T1 - Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

AU - Thurston, David E.

AU - Bose, D. Subhas

AU - Thompson, Andrew S.

AU - Howard, Philip W.

AU - Leoni, Alberto

AU - Croker, Stephen J.

AU - Jenkins, Terrence C.

AU - Neidle, Stephen

AU - Hartley, John A.

AU - Hurley, Laurence H.

PY - 1996/11/15

Y1 - 1996/11/15

N2 - An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The 'amino thioacetal' cyclization procedure was used to produce the electrophilic DNA-interactive N10-C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.

AB - An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The 'amino thioacetal' cyclization procedure was used to produce the electrophilic DNA-interactive N10-C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.

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Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

Abstract

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