126092-97-5Relevant academic research and scientific papers
Synthesis of a mitomycin C-lexitropsin hybrid
Champeil, élise,Sapse, Anne-Marie
, p. 1190 - 1196 (2014)
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.
BENZODIAZEPINE DERIVATIVES
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Page/Page column 138; 148, (2019/07/17)
The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formulae (I), (II) and (III). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.
PBD ANTIBACTERIAL AGENTS
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Page/Page column 84; 85, (2017/07/18)
The invention relates to pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X1, X2, X3 and X4 are connecting functional groups; L is C1-12 alkylene; R4, R5 and R6 are independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5 - to 9 -membered heteroarylene and 5 - to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; R7 is selected from N(C1-6 alkyl)(C1-6alkyl), 5 - to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and R8 and R9 either together form a double bond, or are selected from H and OR14, or R8 is a prodrug moiety and R9 is OR14; m is 0 or 1; with the proviso that when X4 is C(O)NH then the up to three optional substituents of R7 are not selected from (CH2)k -CO2R12; with the proviso that when X4 is (CH2)tO then R4 is not phenylene, m is 1 and R6 is not a 5 - to 9 -membered heteroarylene; and with the proviso that when X4 is C(O)NH or NHC(O) that R4 and/or R6 is not 5 - to 9 -membered heteroarylene.
Synthesis of pyrrole-imidazole polyamide oligomers based on a copper-catalyzed cross-coupling strategy
Shiga, Naoki,Takayanagi, Shihori,Muramoto, Risa,Murakami, Tasuku,Qin, Rui,Suzuki, Yuta,Shinohara, Ken-ichi,Kaneda, Atsushi,Nemoto, Tetsuhiro
, p. 2197 - 2200 (2017/04/27)
Pyrrole-imidazole (Py-Im) polyamides are useful tools for chemical biology and medicinal chemistry studies due to their unique binding properties to the minor groove of DNA. We developed a novel method of synthesizing Py-Im polyamide oligomers based on a Cu-catalyzed cross-coupling strategy. All four patterns of dimer fragments could be synthesized using a Cu-catalyzed Ullmann-type cross-coupling with easily prepared monomer units. Moreover, we demonstrated that pyrrole dimer, trimer, and tetramer building blocks for Py-Im polyamide synthesis were accessible by combining site selective iodination of the pyrrole/pyrrole coupling adduct.
CONJUGATES FOR TREATING DISEASES
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Page/Page column 126, (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.
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.
supporting information, 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.
A modular synthetic route to dimeric calixarenes: A new family of DNA major groove binders
Blecking,Hu,Zadmard,Dasgupta,Schrader
scheme or table, p. 1193 - 1204 (2011/06/17)
We describe here a general strategy for the synthesis of dimeric anilinium/guanidinium calix[4]arenes with aliphatic and heteroaromatic bridges. These compounds display a remarkably high affinity towards double-stranded (ds) DNA and act by a rare mechanism, i.e., insertion into the wide major groove of the nucleic acids. Georg Thieme Verlag Stuttgart New York.
Solution-phase synthesis of pyrrole-imidazole polyamides
Chenoweth, David M.,Harki, Daniel A.,Dervan, Peter B.
experimental part, p. 7175 - 7181 (2009/09/29)
Pyrrole-Imidazole polyamides are DNA-binding molecules that are programmable for a large repertoire of DNA sequences. Typical syntheses of this class of heterocyclic oligomers rely on solid-phase methods. Solid-phasemethodologies offer rapid assembly on a
Discovery of inhibitors of aberrant gene transcription from libraries ofdna binding molecules: Inhibition of LEF-1-mediated gene transcription and oncogenic transformation
Stover, James S.,Shi, Jin,Jin, Wei,Vogt, Peter K.,Boger, Dale L.
supporting information; experimental part, p. 3342 - 3348 (2009/07/30)
The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity (disruption of DNA-LEF-1 binding) at the intended target and site (inhibition of intracellular LEF-1-mediated gene transcription) resulting in a desired phenotypic cellular change (inhibit LEF-1-driven cell transformation) provided two lead compounds: lefmycin-1 and lefmycin-2. The sequence of screens defining the approach assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules. Central to the implementation of this generalized approach to the discovery of DNA binding small molecule inhibitors of gene transcription was (1) the use of a technically nondemanding fluorescent intercalator displacement (FID) assay for initial assessment of the DNA binding affinity and selectivity of a library of compounds for any sequence of interest, and (2) the technology usedto prepare a sufficiently large library of DNA binding compounds.
Synthesis of DNA-sequence-selective hairpin polyamide platinum complexes
Taleb, Robin I.,Jaramillo, David,Wheate, Niai J.,Aldrich-Wright, Janice R.
, p. 3177 - 3186 (2008/02/05)
Two DNA-sequence-selective hairpin polyamide platinum(II) complexes, containing pyrrole and imidazole heterocyclic rings, have been synthesised by different methods. A six-ring complex, selective for (A/T)GGG-(A/T) DNA sequences, was made by using solid-phase synthesis, whilst an eight-ring complex, selective for (A/ T)CCTG(A/T) DNA sequences, was made by utilising standard wet chemistry. Solid-phase synthesis resulted in a significantly higher yield, required less purification and is more efficient than the wet synthesis; as such, it is the preferred method for further work. The metal complexes were characterised by 1H and 195Pt NMR spectroscopy and ESI mass spectrometry. The two compounds provide a foundation for the synthesis of more complex molecules containing multiple hairpins and/or platinum groups.
