126092-99-7Relevant academic research and scientific papers
CONJUGATES FOR TREATING DISEASES
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, (2016/10/04)
The present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.
Synthesis of a mitomycin C-lexitropsin hybrid
Champeil, élise,Sapse, Anne-Marie
, p. 1190 - 1196 (2015/02/05)
We have constructed hybrid drugs where mitomycin C is linked to the N-methylpyrrole carboxamide framework present in lexitropsins. The coupling reactions leading to these products are efficient and the yields are very high. An interesting spectroscopic feature of these hybrids is the red shift observed in the UV-vis spectrum. Although DFT calculations indicate the possible existence of complexes formed during the coupling reactions, these complexes were not detected. The only species produced and isolated were the mitomycin C-mono- and bis-N-methyl pyrrole conjugates.
An extended pyrrolobenzodiazepine-polyamide conjugate with selectivity for a DNA sequence containing the ICB2 transcription factor binding site
Brucoli, Federico,Hawkins, Rachel M.,James, Colin H.,Jackson, Paul J. M.,Wells, Geoff,Jenkins, Terence C.,Ellis, Tom,Kotecha, Minal,Hochhauser, Daniel,Hartley, John A.,Howard, Philip W.,Thurston, David E.
, p. 6339 - 6351 (2013/09/23)
The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase IIα results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectivity of each compound were evaluated in DNA thermal denaturation and DNase I footprinting assays, and the ability to inhibit binding of NF-Y to ICB1 and ICB2 was studied using an electrophoretic mobility shift assay (EMSA). 3a was found to be a potent inhibitor of NF-Y binding, exhibiting a 10-fold selectivity for an ICB2 site compared to an ICB1-containing sequence, and showing low nanomolar cytotoxicity toward human tumor cell lines. Molecular modeling and computational studies have provided details of the covalent attachment process that leads to formation of the PBD-DNA adduct, and have allowed the preference of 3a for ICB2 to be rationalized.
Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates
Wells, Geoff,Martin, Christopher R. H.,Howard, Philip W.,Sands, Zara A.,Laughton, Charles A.,Tiberghien, Arnaud,Woo, Chi Kit,Masterson, Luke A.,Stephenson, Marissa J.,Hartley, John A.,Jenkins, Terence C.,Shnyder, Steven D.,Loadman, Paul M.,Waring, Michael J.,Thurston, David E.
, p. 5442 - 5461 (2007/10/03)
A novel series of methyl ester-terminated CS-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5′-XGXWz (z = 3 ± 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
Total synthesis of distamycin A and 2640 analogues: A solution-phase combinatorial approach to the discovery of new, bioactive DNA binding agents and development of a rapid, high-throughput screen for determining relative DNA binding affinity or DNA binding sequence selectivity
Boger, Dale L.,Fink, Brian E.,Hedrick, Michael P.
, p. 6382 - 6394 (2007/10/03)
The development of a solution-phase synthesis of distamycin A and its extension to the preparation of 2640 analogues are described. Thus, solution-phase synthesis techniques with reaction workup and purification employing acid/base liquid - liquid extractions were used in the multistep preparation of distamycin A (8 steps, 40% overall yield) and a prototypical library of 2640 analogues providing intermediates and final products that are ≥95% pure on conventional reaction scales. The complementary development of a simple, rapid, and high-throughput screen for DNA binding affinity based on the loss of fluorescence derived from displacement of prebound ethidium bromide is disclosed which is applicable for assessing relative or absolute binding affinity to DNA homopolymers or specific sequences (hairpin oligonucleotides). Using hairpin oligonucleotides, this method permits the screening of a library of compounds against a single predefined sequence to identify high affinity binders, or the screening of a single compound against a full library of individual hairpin oligionucleotides to define its sequence selectivity. The combination permits the establishment of the complete DNA binding profile of each member of a library of compounds. Screening the prototypical library provided compounds that are 1000 times more potent than distamycin A in cytotoxic assays (67, IC50 = 29 nM, L1210), that bind to poly[dA]-poly[dT] with comparable affinity, and that exhibit an altered DNA binding sequence selectivity. Several candidates were identified which bound the five-base-pair AT-rich site of the PSA-ARE-3 sequence, and one (128, K = 3.2 x 106 M-1) maintained the high affinity binding (K = 4.5 x 106 M-1) to the ARE-consensus sequence containing a GC base-pair interrupted five-base-pair AT-rich site suitable for inhibition of gene transcription initiated by hormone insensitive androgen receptor dimerization and DNA binding characteristic of therapeutic resistant prostate cancer.
Design, synthesis, DNA binding, and biological activity of a series of DNA minor-groove-binding intercalating drugs
Bailly,Pommery,Houssin,Henichart
, p. 910 - 917 (2007/10/02)
A group of pseudopeptides, molecular combination of the natural antitumor agents distamycin or netropsin and the anilinoacridine chromophore (which is related to the synthetic antileukemic drug amsacrine) has been synthesized. Their DNA binding properties were determined and discussed in terms of their structural differences and in relation to their observed base-dependent binding. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the netropsin or distamycin residue resides in the DNA minor groove. Cytostatic and cytotoxic activities against a murine cell line are reported, as well as significant differences in the inhibition of DNA synthesis.
