Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501)

Cheung, Andrew P.; Struble, Elaine; He, Jingyi; Yang, Chun; Wang, Euphemia; Thurston, David E.; Liu, Paul

doi:10.1016/j.jchromb.2005.04.027

Cited by 10 publications

(12 citation statements)

References 14 publications

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“…An alternative HPLC-based assay was developed to quantify the reactive imine form of SJG-136 which proved to be accurate, reproducible and linear. [85] The metabolism of SJG-136 was also evaluated in a rat liver microsome assay, and it was found to be metabolized by CYP3A isoforms [20] resulting in oxidative cleavage of the C8/ C8'-propyl linker and the release of two PBD monomer units.…”

Section: Preclinical Evaluation Of Sjg-136mentioning

confidence: 99%

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

et al. 2016

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The pyrrolo[2,1‐c][1,4]benzodiazepines (PBDs) are a family of sequence‐selective DNA minor‐groove binding agents that form a covalent aminal bond between their C11‐position and the C2‐NH2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG‐136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor‐targeting antibodies to create antibody–drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre‐clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD‐containing ADCs, and explores both structure–activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.

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Section: Preclinical Evaluation Of Sjg-136mentioning

confidence: 99%

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

et al. 2016

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“…The presence of carbinolamine compounds is not wholly unexpected as they are the intermediate compounds to imine formation via reactions between carbonyl compounds and primary or secondary amines. These compounds have been observed as intermediates in other carbonyl-amine reactions and have been shown to have a slow reverse reaction, remaining stable in solution for up to 24 h (Cheung et al, 2005;Cocivera et al, 1976;Pedersen et al, 1999).…”

Section: Mass Spectrum Interpretationmentioning

confidence: 99%

Secondary organic aerosol formation from primary aliphatic amines with NO<sub>3</sub> radical

Malloy

Warren

et al. 2009

Atmos. Chem. Phys.

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Abstract. Primary aliphatic amines are an important class of nitrogen containing compounds emitted from automobiles, waste treatment facilities and agricultural animal operations. A series of experiments conducted at the UC-Riverside/CE-CERT Environmental Chamber is presented in which oxidation of methylamine, ethylamine, propylamine, and butylamine with O 3 and NO 3 have been investigated. Very little aerosol formation is observed in the presence of O 3 only. However, after addition of NO, and by extension NO 3 , large aerosol mass yields (∼44% for butylamine) are seen. Aerosol generated was determined to be organic in nature due to the small fraction of NO and NO 2 in the total signal (<1% for all amines tested) as detected by an aerosol mass spectrometer (AMS). We propose a reaction mechanism between carbonyl containing species and the parent amine leading to formation of particulate imine products. These findings can have significant impacts on rural communities with elevated nighttime PM loadings, when significant levels of NO 3 exist.

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“…The PBDs, dimers and monomers, contain highly reactive imines in the diazepinone portions of the molecule. Cheung and colleagues have demonstrated that water or alcohol adds readily to the imino moiety of the PBD dimer SJG-136 to form the corresponding carbinolamine or its alkyl ether, respectively (38). Similar results have been demonstrated with the PBD monomers by Antonow and colleagues (personal communication).…”

Section: Discussionmentioning

confidence: 55%

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

Kaliszczak

Antonow

Patel

et al. 2010

AAPS J

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Abstract. Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA crosslinking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P-gp, ABCG2, and MRP1). Isogenic cell lines expressing P-gp and ABCG2, cell lines with acquired resistance to cytotoxic agents due to the high expression of ABC transporters, and specific inhibitors against P-gp, ABCG2, and MRP1 were used. P-gp and ABCG2 decreased the permeability of the PBD dimers across cell membranes and their interaction with DNA, reducing DNA damage and the overall cytotoxic effect. PBD monomer SG-2823 formed a conjugate with glutathione and interacted with MRP1, reducing its cytotoxic effect in A549 cells. Structure-activity relationship revealed that the interaction of PBDs with the transporters could be predicted considering the molecular weight, the lipophilicity, the number of (N+O) atoms and aromatic rings, the polar surface area, the hydrogen bonding energy, and electrophilic centers. A rational design of novel PBDs with increased potency and reduced interaction with the ABC transporters is proposed.

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Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501)

Cited by 10 publications

References 14 publications

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

Secondary organic aerosol formation from primary aliphatic amines with NO<sub>3</sub> radical

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

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Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501)

Cited by 10 publications

References 14 publications

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

Secondary organic aerosol formation from primary aliphatic amines with NO&lt;sub&gt;3&lt;/sub&gt; radical

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

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Secondary organic aerosol formation from primary aliphatic amines with NO<sub>3</sub> radical