- Practical Gram-Scale Synthesis of Iboxamycin, a Potent Antibiotic Candidate
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A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.
- Mason, Jeremy D.,Myers, Andrew G.,Pote, Aditya R.,Terwilliger, Daniel W.
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p. 11019 - 11025
(2021/08/03)
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- LINCOSAMIDE ANTIBIOTICS AND USES THEREOF
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Provided are compounds of Formula (I) for the treatment of infectious and inflammatory diseases. The compounds described herein are lincosamides modified at the amino acid (southern) region. The compounds may have further modification at the C-7 position of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating infectious diseases using the disclosed compounds.
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- FUSED HETEROCYCLIC BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
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- NOVEL BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
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- Scale-up Synthesis of Tesirine
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This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody-drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody-drug conjugates in multiple clinical trials, four of them pivotal.
- Tiberghien, Arnaud C.,Von Bulow, Christina,Barry, Conor,Ge, Huajun,Noti, Christian,Collet Leiris, Florence,McCormick, Marc,Howard, Philip W.,Parker, Jeremy S.
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p. 1241 - 1256
(2018/09/06)
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- An Immucillin-Based Transition-State-Analogous Inhibitor of tRNA-Guanine Transglycosylase (TGT)
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Shigellosis is one of the most severe diarrheal diseases worldwide without any efficient treatment so far. The enzyme tRNA-guanine transglycosylase (TGT) has been identified as a promising target for small-molecule drug design. Herein, we report a transition-state analogue, a small, immucillin-derived inhibitor, as a new lead structure with a novel mode of action. The complex inhibitor synthesis was accomplished in 18 steps with an overall yield of 3 %. A co-crystal structure of the inhibitor bound to Z. mobilis TGT confirmed the predicted conformation of the immucillin derivative in the enzyme active site.
- Hohn, Christoph,H?rtsch, Adrian,Ehrmann, Frederik Rainer,Pfaffeneder, Toni,Trapp, Nils,Dumele, Oliver,Klebe, Gerhard,Diederich, Fran?ois
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p. 6750 - 6754
(2016/05/11)
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- New optically active 4-alkoxyprolinol ethers derived from trans-4-Hydroxy-L-proline
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(2S,4R)-trans-4-Hydroxy-L-proline has been used as thechiral-pool source in the efficient syntheses of optically active protected 4-hydroxyprolinols. After N-acyl protection andester formation, the first ether moiety was introduced maintaining the chiral
- Friedemann, Nora M.,Eustergerling, Astrid,Nubbemeyer, Udo
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experimental part
p. 837 - 843
(2012/03/11)
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- AURORA KINASE COMPOUNDS AND METHODS OF THEIR USE
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Provided herein are pyrrolotriazine compounds for treatment of Aurora kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 217-218
(2011/08/04)
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- Structure-guided minimalist redesign of the L-fuculose-1-phosphate aldolase active site: Expedient synthesis of novel polyhydroxylated pyrrolizidines and their inhibitory properties against glycosidases and intestinal disaccharidases
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A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz = benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N-Cbz-amino aldehydes including N-Cbz-prolinal derivatives. FucA F131A showed an aldol activity of 62μmol-1mg-1 with (R)-N-Cbz-prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)-amino aldehydes gave exclusively the anti configured aldol adducts whereas their 5 counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)and with (S)-N-Cbz-prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N-Cbz-prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π-cation interaction with the residue K205' and to efficient contact between the substrate and the mechanistically important Y113' and Y209' residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) and 1,4-dideoxy-1,4-iminoD-arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.
- Garrabou, Xavier,Gomez, Livia,Joglar, Jesus,Gil, Sergi,Parella, Teodor,Bujons, Jordi,Clapes, Pere
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experimental part
p. 10691 - 10706
(2010/11/19)
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- Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues
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trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.
- Vaněk, Václav,Budě?ínsky, Milo?,Rinnová, Markéta,Rosenberg, Ivan
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experimental part
p. 862 - 876
(2009/05/09)
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- Backbone extended pyrrolidine PNA (bepPNA): A chiral PNA for selective RNA recognition
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Synthesis of cationic, chiral PNA analogues with an extra atom in the backbone (bepPNA) is reported. The (2S,4S) geometry of the pyrrolidine ring, and an additional carbon atom in the backbone of homopyrimidine-bepPNAs resulted in the optimization of the inter-nucleobase distance, such that selective binding to complementary RNA over DNA was observed in the triplex mode. It was evident from circular dichroism studies that oligomers with mixed aminoethylglycyl-bep (aeg-bep) repeating units, and also bepPNA with homogeneous backbone attained structures quite different from those of aegPNA2:RNA/DNA complexes. The bepPNA, when incorporated in a duplex forming mixed purine-pyrimidine sequence, also showed a preference for binding complementary RNA over DNA.
- Govindaraju,Kumar, Vaijayanti A.
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p. 2321 - 2330
(2007/10/03)
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- PROCESS FOR PRODUCING PYRROLIDINE DERIVATIVE
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This invention provides an industrially useful process for producing 1,4-transcyclohexanecarboxylic acid derivative (1) which has excellent VLA-4 inhibitory action and safety, and an intermediate which is useful in such method. More particularly, this inv
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Page/Page column 20-21
(2010/11/08)
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- PYRROLOBENZODIAZEPINE DERIVATIVES, COMPOSITIONS COMPRISING THE SAME AND METHODS RELATED THERETO
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Disclosed are compounds of Formula (I) wherein X, Y, R1-R7, T1, T2, Z, and p are as described herein; a pharmaceutical composition comprising a compound of Formula (I) and a carrier; a method of inhibiting growth of a cell, which method comprises administering in an amount effective to inhibit growth a compound of Formula (I); a method of treating cancer in a mammal, which method comprises administering in an amount effective to treat cancer a compound of Formula (I); a method of treating a viral, parasitic, or bacterial infection of a cell, which method comprises administering in an amount effective to treat a viral, parasitic, or bacterial infection a compound of Formula (I); and a method of preparing a compound of Formula (I) as described herein.
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Page/Page column 33-34
(2008/06/13)
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- Backbone-extended pyrrolidine peptide nucleic acids (bepPNA): Design, synthesis and DNA/RNA binding studies
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One-carbon extended conformationally constrained pyrrolidine PNA monomer (bepPNA) has been synthesized, incorporated into PNA sequences at predefined positions, and showed selective RNA binding properties.
- Govindaraju,Kumar, Vaijayanti A.
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p. 495 - 497
(2008/09/18)
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- Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8′ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers
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A C2/C2′-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)nO-C8′ diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., > 3400-fold in IGRO
- Gregson, Stephen J.,Howard, Philip W.,Gullick, Darren R.,Hamaguchi, Anzu,Corcoran, Kathryn E.,Brooks, Natalie A.,Hartley, John A.,Jenkins, Terence C.,Patel, Sejal,Guille, Matthew J.,Thurston, David E.
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p. 1161 - 1174
(2007/10/03)
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- Synthesis of trans-L/D-2-(tert-butoxycarbonylaminomethyl)-4-(thymin-1-yl) pyrrolidin-1-yl acetic acid
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To delineate the binding preferences of stereochemically divergent pyrrolidine PNAs, synthesis of all four diastreomeric monomers of I and the systematic complexation studies of the resultant PNAs with complementary DNA/ RNA is essential. We herein report the synthesis of trans-L/D-2-(tert-butoxycarbonylaminomethyl)-4-(thymin-1-yl) pyrrolidin-1-yl acetic acids I, their incorporation in PNA oligomers and DNA binding studies will be presented.
- Kumar, Vaijayanti A.,Meena
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p. 1285 - 1288
(2007/10/03)
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- Pyrrolobenzodiazepines
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Compounds of the formulae Ia and Ib: wherein:A is CH2, or a single bond;R2 is selected from: R, OH, OR, CO2H, CO2R, COH, COR, SO2R, CN;R6, R7 and R9 are independently selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn;and R8 is selected from H, R, OH, OR, halo, amino, NHR, nitro, Me3Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula Ia or Ib, where the R8 groups of the monomers form together a bridge having the formula -X-R'-X- linking the monomers, where R' is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero-atoms and/or aromatic rings and may contain one or more carbon-carbon double or triple bonds, and each X is independently selected from O, S, or N; except that in a compound of formula Ia when A is a single bond, then R2 is not CH=CH(CONH2) or CH=CH(CONMe2). Other related compounds are also disclosed.
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Page 14, 36, 105
(2010/11/29)
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- Effect of C2-exo unsaturation on the cytotoxicity and DNA-binding reactivity of pyrrolo[2,1-c][1,4]benzodiazepines
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A series of novel C2-exo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) has been synthesised via a versatile pro-C2 ketone precursor. C2-exo-unsaturation enhances both DNA-binding reactivity and in vitro cytotoxic potency. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Gregson, Stephen J.,Howard, Philip W.,Corcoran, Kathryn E.,Barcella, Simona,Yasin, Maqsood M.,Hurst, Abigail A.,Jenkins, Terence C.,Kelland, Lloyd R.,Thurston, David E.
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p. 1845 - 1847
(2007/10/03)
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- Oligonucleotide analogues with 4-hydroxy-N-acetylprolinol as sugar substitute
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Modified oligonucleotides incorporating trans-4-hydroxy-N-acetyl-L-prolinol (trans-4-HO-L-NAP) or its D-analogue as sugar substitute were synthesised with adenine and thymine as nucleobases. All-adenine oligonucleotides built from (2S,4S) or (2R,4R)-cis-4
- Ceulemans, Griet,Van Aerschot, Arthur,Wroblowski, Berthold,Rozenski, Jef,Hendrix, Chris,Herdewijn, Piet
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p. 1997 - 2010
(2007/10/03)
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- Nucleosides and Oligonucleotides Derived from trans-4-Hydroxy-N-acetylprolinol
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The 4-O-phosphoramidites of monomethoxytritylated 4-hydroxy-N-6-benzoyladenin-9-yl)acetyl>prolinol and 4-hydroxy-N-prolinol were prepared for incorporation into nucleic acids.The L-trans all-adenine oligonucleotide (ON) hybridises to natural oligothymidylate, apparently via triplex formation.All-purine sequences of the L-trans form can also form homo-complexes with their pyrimidine counterpart.The D-trans compounds give larger destabilisation when inserted in DNA.D-trans all-adenine ONs do not form complexes with natural oligothymidylate.For this series of modified ONs no hybridisation could be detected between complementary strands of opposite enantiomeric form.
- Ceulemans, G.,Aerschot, A. Van,Herdewijn, P.
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p. S234 - S237
(2007/10/03)
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- Solid support for synthesis of 3'-tailed oligonucleotides
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A solid support for oligonucleotide synthesis has the structure STR1 where CPG represents a controlled pore glass matrix, the wavy line represents a carbon chain covalently linking the NH group with the controlled pore glass matrix, X is 2,2'-dimethoxytri
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- Preparation of 2,5-diazabicyclo[2.2.1]heptanes and intermediates
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(R,R)-2,5-Diazabicyclo[ 2.2.1]heptanes are prepared from a compound of the formula STR1 wherein X and R2 are as defined herein, by heating with tosylchloride in pyridine, reacting the formed compound of the formula STR2 with a C1 -C6 alkylamine or ammonia, and reducing or hydrolyzing the formed compound of the formula STR3 wherein R1 is hydrogen or C1 -C6 alkyl.
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- Antiarrhythmic agents
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The invention provides antiarrhythmic agents of the formula:- or a pharmaceuticaliy acceptable salt thereof, wherein R1 is C1-C4 alkyl; X is -(CH2)2-, -CH(OH)CH2-, -COCH2- or a direct link;
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- AN ENANTIOSELECTIVE SYNTHESIS OF (+)-CROTANECINE
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(2S,4R)-4-Hydroxyproline was elaborated into (+)-crotanecine via (1S,5R,8R)-8-hydroxy-2-oxa-6-azabicyclooctan-3-one
- Yadav, Veejendra Kumar,Rueeger, Heinrich,Benn, Michael
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p. 2735 - 2738
(2007/10/02)
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