Synthesis of a novel C2/C2′-exo unsaturated pyrrolobenzodiazepine cross-linking agent with remarkable DNA binding affinity and cytotoxicity

Gregson, Stephen J.; Howard, Philip W.; Thurston, David E.; Jenkins, Terence C.; Kèlland, Lloyd R.

doi:10.1039/a809791g

Cited by 48 publications

(47 citation statements)

References 13 publications

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“…The pyrrolo [2,1-c](1,4)benzodiazepine dimer, SJG-136 (NSC 694501), initially was synthesized (3,4) and supplied by David E. Thurston and colleagues of the Cancer Research UK Gene Targeted Drug Design Research Group, School of Pharmacy, University of London to the United States NCI. These materials were inventoried by the Drug Synthesis and Chemistry Branch of the Developmental Therapeutics Program, NCI as samples 1 and 2 (absolute purity values unknown but Ͼ85%).…”

Section: Methodsmentioning

confidence: 99%

SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

Alley

Hollingshead²,

Pacula-Cox³

et al. 2004

Cancer Research

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Section: Methodsmentioning

confidence: 99%

SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

Alley

Hollingshead²,

Pacula-Cox³

et al. 2004

Cancer Research

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“…The synthesis and chemical characterization of SJG-136 have been documented elsewhere (13,15). Stock solutions, unless otherwise indicated, were prepared in analytical grade methanol and stored dry at Ϫ20°C.…”

Section: Methodsmentioning

confidence: 99%

“…Second generation molecules were designed and synthesized, which were unsaturated at the C2/C2Ј positions (13) in an attempt to produce lower electrophilicity at the N10-C11 positions within the molecule to decrease deactivation by cellular nucleophiles (14). A resulting C2-exo-methylene PBD dimer, SJG-136 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

et al. 2004

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“…The two imine moieties at the top of each seven-membered ring of SJG-136 bind covalently to the N2 positions of guanines on opposite strands of DNA to form a cytotoxic interstrand crosslink spanning four base pairs (4).…”

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confidence: 99%

Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors

Hochhauser

Meyer

Spanswick

et al. 2009

Clinical Cancer Research

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Purpose:This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. Experimental Design: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 Ag/m 2 ) given as a 10-minute i.v. infusion every 21days. The dose was subsequently reduced in incremental steps to 45 Ag/m 2 due to unexpected toxicity. Results:The maximum tolerated dose of SJG-136 was 45 Ag/m 2 .The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive g-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. Conclusions: SJG-136 was associated with dose-limitingVLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

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Synthesis of a novel C2/C2′-exo unsaturated pyrrolobenzodiazepine cross-linking agent with remarkable DNA binding affinity and cytotoxicity

Abstract: A C2/C2A-exo unsaturated pyrrolobenzodiazepine dimer 1 has been synthesised which is cytotoxic at the picomolar level and has remarkable covalent DNA binding affinity, raising the melting temperature of duplex-form calf thymus DNA by 34 °C after 18 h incubation.

Cited by 48 publications

References 13 publications

SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors

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