• Corpus ID: 8068004

Cancer esearch apeutics , Targets , and Chemical Biology 285 , a Novel C 2-Aryl-Substituted Pyrrolobenzodiazepine er Prodrug That Cross-links DNA and Exerts Highly R ent Antitumor Activity

@inproceedings{John2010CancerEA,
  title={Cancer esearch apeutics , Targets , and Chemical Biology 285 , a Novel C 2-Aryl-Substituted Pyrrolobenzodiazepine er Prodrug That Cross-links DNA and Exerts Highly R ent Antitumor Activity},
  author={John and Zhizh and Janet and David and Anna Hartley and Anzu Hamaguchi and Marissa Coffils and Christopher R. H. Martin and Marie Suggitt and I Chen and Stephen J Gregson and Luke Masterson and Arnaud C Tiberghien and Maryalice Hartley and Chris J Pepper and Thet Thet Lin and Christopher Fegan and Erin L Thurston and Philip Howard},
  year={2010}
}
ownloade pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, 0) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the o C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble g of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are ated, the imine moieties can bind covalently in the DNA minor groove, forming an… 

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References

SHOWING 1-10 OF 30 REFERENCES
SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity
TLDR
Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, planned to commence shortly.
SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity
TLDR
Compare and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJg-136 does not fit within the clusters of any known agents, suggesting that SJG -136 possesses a distinct mechanism of action.
Pyrrolo[1,4]benzodiazepine antitumor antibiotics: relationship of DNA alkylation and sequence specificity to the biological activity of natural and synthetic compounds.
TLDR
It is determined that the degree of saturation in the five-membered ring of the P(1,4)Bs has a significant effect on the DNA bonding reactivity and biological activity of this class of compounds.
The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136
TLDR
SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove.
Sequence-selective interaction of the minor-groove interstrand cross-linking agent SJG-136 with naked and cellular DNA: footprinting and enzyme inhibition studies.
TLDR
Footprinting studies have confirmed that high-affinity adducts do form at 5'-G-GATC-C-3' sequences and that these can inhibit RNA polymerase in a sequence-selective manner and SJG-136 efficiently inhibits the action of restriction endonuclease BglII.
Sequence-selective recognition of duplex DNA through covalent interstrand cross-linking: kinetic and molecular modeling studies with pyrrolobenzodiazepine dimers.
TLDR
Members of a homologous series of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers with C8-O-(CH(2))(n)-O-C8' diether linkages have been studied for their ability to interact with oligonucleotide duplexes containing potential target binding sites.
A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors
TLDR
For patients with advanced solid tumors, the maximum-tolerated dose of SJG-136 is 40 μg/m2/day administered on days 1, 8 and 15 of a 28-day cycle, and the major dose limiting toxicity was fatigue.
Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin.
TLDR
It is found that the repair of cisplatin adducts does not involve the formation of DNA double-strand breaks, and is likely results from a defect other than in excision repair.
Final results of phase I and pharmacokinetic trial of SJG-136 administered on a daily x 3 schedule
TLDR
Results of a daily x 3 schedule with dexamethasone premedication (dex) and diuretic support with SJG-136 are reported, showing a broad antitumor activity in refractory solid tumors.
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