- Phototriggered labeling and crosslinking by 2-nitrobenzyl alcohol derivatives with amine selectivity
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Here we report the use of 2-nitrobenzyl alcohol (NB) as a photoreactive group with amine selectivity and explore its applications for photoaffinity labeling and crosslinking of biomolecules. This work confirms that NB is an efficient photoreactive group a
- Wang, Chenxi,Liu, Yuan,Bao, Chunyan,Xue, Yuan,Zhou, Yaowu,Zhang, Dasheng,Lin, Qiuning,Zhu, Linyong
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- POLYCYCLIC AMIDES AS CYTOTOXIC AGENTS
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The invention relates to a compound of formula (I): or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or mixtures thereof; wherein the fused ring moiety is a non-alkylating moiety; and wherein the compounds are useful as medicaments, in particular for use as a drug in an antibody-drug conjugate and in the treatment of a proliferative disease, a bacterial infection, a malarial infection and inflammation.
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Page/Page column 165-166
(2020/03/29)
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- PYRROLOBENZODIAZEPINE DERIVATIVES AS INHIBITORS OF NF-KAPPA B FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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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
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Page/Page column 38
(2020/08/13)
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- New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria
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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.
- 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
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supporting information
p. 6941 - 6958
(2020/08/14)
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- In water alkylation of amines with alcohols through a borrowing hydrogen process catalysed by ruthenium nanoparticles
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A simple and environmentally benign procedure for the synthesis of secondary amines in water has been developed. Combining Ru3(CO)12, tetraphenylcyclopentadienone and a small quantity of TGPS-750-M surfactant, primary and secondary alcohols were alkylated at N employing equimolar amounts of aromatic amines in water. The reaction occurs under microwave (MW) dielectric heating with high conversion and high yield. When required, the use of biomass-derived 2-MeTHF or GVL as a co-solvent is possible. Under the influence of MWs, a Ru nanoparticle-nanomicelle combination was formed acting as an effective and recyclable catalyst. This protocol was also employed for "in water" cyclisation to synthesise biologically relevant pyrrolobenzodiazepines (PBDs).
- Risi, Caterina,Calamante, Massimo,Cini, Elena,Faltoni, Valentina,Petricci, Elena,Rosati, Filippo,Taddei, Maurizio
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supporting information
p. 327 - 331
(2020/02/13)
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- Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)
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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.
- Corcoran, David B.,Lewis, Thomas,Nahar, Kazi S.,Jamshidi, Shirin,Fegan, Christopher,Pepper, Chris,Thurston, David E.,Rahman, Khondaker Miraz.
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supporting information
p. 2127 - 2139
(2019/02/26)
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- C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug Resistant Gram-Positive Bacteria
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Antimicrobial resistance has become a major global concern. Development of novel antimicrobial agents for the treatment of infections caused by multidrug resistant (MDR) pathogens is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents initially discovered and isolated from natural sources. Recently, C8-linked PBD biaryl conjugates have been shown to be active against some MDR Gram-positive strains. To explore the role of building block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied. The compounds showed minimum inhibitory concentrations (MICs) in the range of 0.125-32 μg/mL against MDR Gram-positive strains with a bactericidal mode of action. The results showed that a single inversion of amide bonds reduces the activity while the double inversion restores the activity against MDR pathogens. All inverted compounds did not stabilize DNA and lacked eukaryotic toxicity. The compounds inhibit DNA gyrase in vitro, and the most potent compound was equally active against both wild-Type and mutant DNA gyrase in a biochemical assay. The observed activity of the compounds against methicillin resistant S. aureus (MRSA) strains with equivalent gyrase mutations is consistent with gyrase inhibition being the mechanism of action in vivo, although this has not been definitively confirmed in whole cells. This conclusion is supported by a molecular modeling study showing interaction of the compounds with wild-Type and mutant gyrases. This study provides important SAR information about this new class of antibacterial agents.
- Andriollo, Paolo,Hind, Charlotte K.,Picconi, Pietro,Nahar, Kazi S.,Jamshidi, Shirin,Varsha, Amrit,Clifford, Melanie,Sutton, J. Mark,Rahman, Khondaker Miraz
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p. 158 - 174
(2018/02/14)
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- PIPERIDINOBENZODIAZEPINE COMPOUNDS WITH ANTI PROLIFERATIVE ACTIVITY
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The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7-6-membered rings linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs may be represented by formula (I): and salts and solvates thereof, wherein the dotted lines indicates the optional presence of a double bond between one or more of Ci and C2, C2and C3, and C3and C4; R1 and R2 are substituent groups; R3 is selected from H, C1-12 alkyl and CH2Ph; R4is selected from phenyl and C5-9heteroaryl groups optionally substituted, with the proviso that the optionally substituted C5-9heteroaryl is not indolyl; R19is selected from H and (CH2)t-NR20R21; Yiis N or CH; Y2 is N or CH; and wherein at least one of Y1and Y2 is CH; p is o or1; X1 is a connecting group; L is a linker group; X2 is a connecting group or is absent; q is selected from o,1, 2, 3,4,5and 6; A is selected from: for each Ai group one of Y3and Y4is selected from N-R17,S and O; and the other of Y3and Y4is CH; and Y5is selected from CH, N, S and COH; for each A2group one of Y6and Y7is independently selected from N and CH; and the other of Y6and Y7is CH; R13, R14, R17, R2oand R2iare independently selected from H and C1-6alkyl; and either: (i) R5and R6together form a double bond; (ii) R5is H and R6is OH; or (iii) R5is H and R6is OC1-6alkyl; with the proviso that when p is o and A is Ai, then: (a) for at least one Ai group one of Y3and Y4is selected from S and O; or (b) for at least one Ai group Y5is S; or (c) R4is not pyrrolyl, imidazolyl, optionally substituted pyrrolyl or optionally substituted imidazolyl.
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Page/Page column 53; 54
(2017/03/14)
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- ASYMMETRIC CONJUGATE COMPOUNDS
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The invention relates to compound of formula (I): A-X1-L-X2-B and salts, solvates and tautomers thereof, which are useful as medicaments, in particular as anti-proliferative agents and for use as a drug in an antibody-drug conjugate;
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Page/Page column 163
(2017/12/01)
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- PBD ANTIBACTERIAL AGENTS
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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.
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Page/Page column 56; 57
(2017/07/18)
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- A PEGylated photocleavable auxiliary mediates the sequential enzymatic glycosylation and native chemical ligation of peptides
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Research aimed at understanding the specific role of glycosylation patterns in protein function would greatly benefit from additional approaches allowing direct access to homogeneous glycoproteins. Herein the development and application of an efficient approach for the synthesis of complex homogenously glycosylated peptides based on a multifunctional photocleavable auxiliary is described. The presence of a PEG polymer within the auxiliary enables sequential enzymatic glycosylation and straightforward isolation in excellent yields. The auxiliary-modified peptides can be directly used in native chemical ligations with peptide thioesters easily obtained by direct hydrazinolysis of the respective glycosylated peptidyl resins and subsequent oxidation. The ligated glycopeptides can be smoothly deprotected by UV irradiation. We apply this approach to the preparation of variants of the epithelial tumor marker MUC1 carrying one or more Tn, T, or sialyl-T antigens. Two in one: An efficient approach for the preparation of modified peptides has been applied to the synthesis of O-glycosylated MUC1 repeats. A photocleavable PEGylated auxiliary mediates the sequential O-glycosylation and subsequent ligation of MUC1 peptides.
- Bello, Claudia,Wang, Shuo,Meng, Lu,Moremen, Kelley W.,Becker, Christian F. W.
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supporting information
(2015/06/25)
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- GC-Targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models
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DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce
- Rahman, Khondaker M.,Jackson, Paul J. M.,James, Colin H.,Basu, B. Piku,Hartley, John A.,De La Fuente, Maria,Schatzlein, Andreas,Robson, Mathew,Pedley, R. Barbara,Pepper, Chris,Fox, Keith R.,Howard, Philip W.,Thurston, David E.
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supporting information
p. 2911 - 2935
(2013/05/23)
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- (Bio)molecular surface patterning by phototriggered oxime ligation
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Making light work of ligation: A novel method utilizes light for oxime ligation chemistry. A quantitative, low-energy photodeprotection generates aldehyde, which subsequently reacts with aminooxy moieties. The spatial control allows patterning on surfaces (see scheme) with a fluoro marker and GRGSGR peptide, and can be imaged by time-of-flight secondary-ion mass spectrometry. Copyright
- Pauloehrl, Thomas,Delaittre, Guillaume,Bruns, Michael,Mei?ler, Maria,B?rner, Hans G.,Bastmeyer, Martin,Barner-Kowollik, Christopher
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supporting information
p. 9181 - 9184
(2012/11/07)
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- ALKYL 4- [4- (5-OXO-2, 3, 5, 11A-TETRAHYD0-5H-PYRR0L0 [2, 1-C] [1, 4] BENZODIAZEPINE-8-YLOXY) -BUTYRYLAMINO]-1H-PYRROLE-2-CARBOXYLATE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF A PROLIFERATIVE DISEASE
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A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R2 is selected from -H, -OH, =0, =CH2, -CN, -R, OR, halo, =CH-R, O-SO2-R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo, where R and R' are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and YRY, where Y is selected from O, S and NH and RY is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and RE is C1-4 alkyl. The compound is useful for the treatment of proliferative diseases.
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Page/Page column 37; 38
(2008/06/13)
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- Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates
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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.
- 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.
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p. 5442 - 5461
(2007/10/03)
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- SYNTHESIS OF PROTECTED PYRROLOBENZODIAZEPINES
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A method of synthesis of a N-10 protected PBD compound of formula (I) via an intermediate of formula (II) or formula (V).
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Page/Page column 49-50
(2010/02/11)
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- Novel solid phase synthesis supports for the preparation of oligonucleotides containing 3'-alkyl amines
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The synthesis and application of photolabile supports for solid phase oligonucleotide synthesis that release oligonucleotides containing 3'-alkyl amines is described. The alkyl amine functionality can be revealed without removing any other protecting groups throughout the biopolymer. The solid phase synthesis supports do not contain a nucleoside, making it possible to use a single support for the synthesis of oligonucleotides independent of their sequence. Individual solid phase synthesis supports differ according to the length of the alkyl tether between the 4,4'-dimethoxytrityl group which serves as the initiation site for oligonucleotide synthesis and the latent alkyl amine. Eicosameric oligonucleotides are obtained in yields ranging from 70-98% under photolysis conditions that are known to produce less than 3% thymidine·thymidine photodimers. Longer oligonucleotides (30 and 40 nucleotides in length) are cleaved from these solid phase synthesis supports in lower yields.
- McMinn,Greenberg
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p. 3827 - 3840
(2007/10/03)
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- Facile synthesis of a o-nitrobenzyl photolabile linker for combinatorial chemistry
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Two facile syntheses are described of the o-nitrobenzyl alcohol photolabile linker (5). This compound is a valuable intermediate in the preparation of combinatorial libraries, where it allows release from the solid support to give libraries of acids.
- Teague, Simon J.
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p. 5751 - 5754
(2007/10/03)
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