- One-pot preparation of N-carbamate protected amino acids via the azide
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A convenient and efficient method for the preparation of fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc) amino acids is proposed. This method is particularly attractive due to the fact that the reaction sequence Fmoc/Alloc-chloride to Fmoc/Alloc-azide to Fmoc/Alloc-amino acid can readily be carried out in one pot. A further advantage is the minimization of byproducts, which are easily removed during the workup. Most important, this strategy minimizes the formation of dipeptides that are difficult to remove by crystallization. Thus, Fmoc and Alloc amino acids are obtained in high yield (60-90%) and purity as evidenced by thin-layer chromatography, reversed-phase high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance.
- Cruz, Luis J.,Beteta, Natalia G.,Ewenson, Ariel,Albericio, Fernando
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Read Online
- DIALLYL DICARBONATE. A CONVENIENT REAGENT FOR THE SYNTHESIS OF ALLYL CARBAMATES
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Diallyldicarbonate was prepared and used for the amino protection of various compounds including amino acids, amino sugars and nucleosides.
- Sennyey, Gerard,Barcelo, Gerard,Senet,Jean-Pierre
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Read Online
- CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES
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A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
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Page/Page column 160
(2020/01/31)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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Page/Page column 305-306
(2020/05/19)
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- Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin
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The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and a bulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days.
- Hawkins, Paige M. E.,Tran, Wendy,Nagalingam, Gayathri,Cheung, Chen-Yi,Giltrap, Andrew M.,Cook, Gregory M.,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 15200 - 15205
(2020/10/23)
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- PYRROLOBENZODIAZEPINE ANTIBODY CONJUGATES
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The present disclosure relates generally to antibody-drug conjugates comprising pyrrolo[2, 1-c][1, 4]benzodiazepine (PBD) drug moieties. The present disclosure also relates to methods of using these conjugates, e.g., as therapeutics and/or diagnostics.
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Paragraph 01087
(2019/06/11)
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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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- Total Synthesis of Ecumicin
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The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM).
- Hawkins, Paige M. E.,Giltrap, Andrew M.,Nagalingam, Gayathri,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 1019 - 1022
(2018/02/23)
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- PYRROLOBENZODIAZEPINE CONJUGATES
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A compound of formula (I) : (I) and its conjugates.
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Page/Page column 142; 143
(2018/04/27)
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- Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin
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A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro.
- Kemp, Gary C.,Tiberghien, Arnaud C.,Patel, Neki V.,D'Hooge, Francois,Nilapwar, Sanjay M.,Adams, Lauren R.,Corbett, Simon,Williams, David G.,Hartley, John A.,Howard, Philip W.
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p. 1154 - 1158
(2017/06/21)
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- PYRROLOBENZODIAZEPINE CONJUGATES
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A conjugate of formula (I), wherein L is a Ligand unit, D is a Drug Linker unit of formula (II), wherein either: (a) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (b)
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Page/Page column 103
(2017/09/05)
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- PYRROLOBENZODIAZEPINE ANTI-HER2 ANTIBODY CONJUGATES
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A conjugate of formula (I) L - (DL)p (I) wherein L is an antibody (Ab) which binds HER2, D is a Drug Linker unit of formula (A) wherein p is an integer of from 1 to 20.
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Page/Page column 41
(2017/09/07)
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- Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation
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The preparation of peptide fragments containing dehydrovaline and dehydroisoleucine moieties present in the antibiotic myxovalargin is reported. Peptide formation is based on a copper-mediated C-N cross-coupling protocol between an acyl amide and a peptidic vinyl iodide. The presence of a neighboring arginine in the vinyl iodide posed a challenge with respect to the choice of the protecting group and the reaction conditions. It was found that ornithine - a suitable precursor - is better suited than arginine for achieving good yields for the C-N cross-coupling reaction. The optimized conditions were utilized for the synthesis of peptides 32, 33, 39 and 40 containing a neighboring ornithine as well as for the tripeptide 44 containing dehydroisoleucine with the correct stereochemistry.
- Gille, Franziska,Kirschning, Andreas
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supporting information
p. 564 - 570
(2016/04/08)
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- ANTIBODIES AND ANTIBODY-DRUG CONJUGATES
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This application provides antibodies and antigen binding fragments thereof which are capable of specifically binding the 5T4 cell surface antigen, antibody-drug conjugates, and antibody-imaging agent conjugates, as well as means and methods for producing and using them.
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Paragraph 0529
(2015/11/03)
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- HUMANIZED ANTI-TN-MUC1 ANTIBODIES AND THEIR CONJUGATES
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Humanized anti-Tn-MUC1 antibodies and conjugates thereof. Conjugates comprising pyrrolobenzodiazepines (PBDs) having a labile protecting group in the form of a linker to the antibody are described.
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Page/Page column 192
(2015/11/09)
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- NOVEL ANTIBODY CONJUGATES AND USES THEREOF
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Provided are novel antibody drug conjugates (ADCs), and methods of using such ADCs to treat proliferative disorders.
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Page/Page column 157
(2014/09/03)
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- SYNTHESIS METHOD AND INTERMEDIATES USEFUL IN THE PREPARATION OF PYRROLOBENZODIAZEPINES
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A compound of formula I wherein: R7 is selected from: ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH2; -CH2-O-C(=O)Me; R8 is OProt°, where Prot° is a silicon-based oxygen protecting group orthogonal to Rc; R9 is selected from H, methyl and methoxy; Rs is selected from CF3, (CF2)3CF3, CH3 and (formula 2) and Rc is selected from: (i) -C(=O)-ORC1, where RC1 is a saturated C1-4 alkyl group; (ii) -CH2-O-C(=0)RC2, where RC2 is methyl or phenyl; (iii) -CH2-O-Si-(RSi1)(RSi2)(RSi3), where RSi1, RSi2, RSi3 are independently selected from C1-6 a saturated alkyl group and a phenyl group; and (iv) -C(-YRC3)(-YRC4) where each Y is independently O or S, and where RC3 and RC4 are independently a saturated C1-4 alkyl group, or together form a C2-3 alkylene.
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Page/Page column 90; 91
(2013/04/25)
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- HCV NS3 PROTEASE INHIBITORS
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The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column 39
(2008/12/05)
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- Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (β-secretase)
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A series of novel macrocyclic amide-urethanes was designed and synthesized based upon the X-ray crystal structure. Inhibitors containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against memapsin 2. A series of novel macrocycli
- Ghosh, Arun K.,Devasamudram, Thippeswamy,Hong, Lin,Dezutter, Christopher,Xu, Xiaoming,Weerasena, Vajira,Koelsch, Gerald,Bilcer, Geoffrey,Tang, Jordan
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- Synthesis of a PNA-encoded cysteine protease inhibitor library
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Peptide nucleic acids (PNAs) have been used to encode a combinatorial library whereby each compound is labeled with a PNA tag which reflects its synthetic history and localizes the compound upon hybridization to an oligonucleotide array. We report herein
- Debaene, Fran?ois,Mejias, Lorenzo,Harris, Jennifer L.,Winssinger, Nicolas
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p. 8677 - 8690
(2007/10/03)
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- New polymer-supported allyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc) amino-protecting reagents
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New polymer-supported reagents, Alloc-P-OSu and Proc-P-OSu, have been prepared from a polymeric N-hydroxysuccinimide (P-HOSu), and used as solid-supported reagents for the allyloxycarbonyl (Alloc) and propargyloxycarbonyl (Proc) protection of the amino group. These new polymeric reagents are safe and stable, the residual P-HOSu generated after the protection reaction can be easily separated by simple filtration and reused.
- Chinchilla, Rafael,Dodsworth, David J.,Nájera, Carmen,Soriano, José M.
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p. 809 - 812
(2007/10/03)
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- Employing the structural diversity of nature: Development of modular dipeptide-analogue ligands for ruthenium-catalyzed enantioselective transfer hydrogenation of ketones
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A library of novel dipeptideanalogue ligands based on the combination of tert-butoxycarbonyl(N-Boc)-protected a-amino acids and chiral vicinal amino alcohols were prepared. These highly modular ligands were combined with [{RuCl2(p-cymene)}2 and the resulting metal complexes were screened as catalysts for the enantioselective reduction of acetophenone under transfer hydrogenation conditions using 2-propanol as the hydrogen donor. Excellent enantioselectivity of 1-phenylethanol (up to 98% ee) was achieved with several of the novel catalysts. Although most of the ligands contained two stereocenters, it was demonstrated that the absolute configuration of the product alcohol was determined by the configuration of the amino acid part of the ligand. Employing ligands based on L-amino acids generated S-configured products, and catalysts based on Damino acids favored the formation of the R-configured alcohol. The combination N-Boc-L-alanine and (R)-phenylglycinol (Boc-L-Ab) or its enantiomer (N-Boc-D-alanine and (S)-phenylglycinol, Boc-D-Aa) proved to be the best ligands for the reduction process. Transfer hydrogenation of a number of aryl alkyl ketones were evaluated and excellent enantioselectivity, up to 96 % ee, was obtained.
- Pastor, Isidro M.,Vaestilae, Patrik,Adolfsson, Hans
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p. 4031 - 4045
(2007/10/03)
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- Antiretroviral hydrazine derivatives
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The invention relates to compounds of formula STR1 and salts, pharmaceutical compositions, intermediates and processes of preparation thereof.
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- Aza-peptide analogs as potent human immunodeficiency virus type-1 protease inhibitors with oral bioavailability
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A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isostere has been synthesized as HIV-1 protease inhibitors using a simple synthetic scheme. Structure-activity studies based on the X-ray of a previously described inhibitor-enzyme complex led to potent inhibitors with antiviral activity in the low-nanomolar range. The S-configuration of the transition- state hydroxyl group was preferred in this series. Small modifications of the P2P3 and P2'P3' substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound 8a and its close analog 24a bearing a methyl carbamate in P3 and an ethyl carbamate in P3' position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED50 values 150-fold following oral application in mice.
- F?ssler, Alexander,Bold, Guido,Capraro, Hans-Georg,Cozens, Robert,Mestan, Jürgen,Poncioni, Bernard,R?sel, Johannes,Tintelnot-Blomley, Marina,Lang, Marc
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p. 3203 - 3216
(2007/10/03)
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