909415-14-1Relevant articles and documents
New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria
Picconi, Pietro,Hind, Charlotte K.,Nahar, Kazi S.,Jamshidi, Shirin,Di Maggio, Lucia,Saeed, Naima,Evans, Bonnie,Solomons, Jessica,Wand, Matthew E.,Sutton, J. Mark,Rahman, Khondaker Miraz
, p. 6941 - 6958 (2020)
It is urgent to find new antibiotic classes with activity against multidrug-resistant (MDR) Gram-negative pathogens as the pipeline of antibiotics is essentially empty. Modified pyrrolobenzodiazepines with a C8-linked aliphatic heterocycle provide a new class of broad-spectrum antibacterial agents with activity against MDR Gram-negative bacteria, including WHO priority pathogens. The structure-activity relationship established that the third ring was particularly important for Gram-negative activity. Minimum inhibitory concentrations for the lead compounds ranged from 0.125 to 2 mg/L for MDR Gram-negative, excluding Pseudomonas aeruginosa, and between 0.03 and 1 mg/L for MDR Gram-positive species. The lead compounds were rapidly bactericidal with >5 log reduction in viable count within 4 h for Acinetobacter baumannii and Klebsiella pneumoniae. The lead compound inhibited DNA gyrase in gel-based assays, with an IC50 of 3.16 ± 1.36 mg/L. This study provides a new chemical scaffold for developing novel broad-spectrum antibiotics which can help replenish the pipeline of antibiotics.
PYRROLOBENZODIAZEPINE DERIVATIVES AS INHIBITORS OF NF-KAPPA B FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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Page/Page column 39, (2020/08/13)
The invention relates to a compound of formula (I) or salts, solvates, stereoisomers, tautomers or combinations thereof, wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and
Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)
Corcoran, David B.,Lewis, Thomas,Nahar, Kazi S.,Jamshidi, Shirin,Fegan, Christopher,Pepper, Chris,Thurston, David E.,Rahman, Khondaker Miraz.
supporting information, p. 2127 - 2139 (2019/02/26)
The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the noncovalent element of the molecule on transcription factor inhibitory capacity were also explored through an enzyme-linked immunosorbent assay-based measurement of nuclear NF-κB upon exposure of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold because of their potent cytotoxicity and drug-like properties.
