- PYRROLOBENZODIAZEPINE DIMER PRECURSOR AND LIGAND-LINKER CONJUGATE COMPOUND THEREOF
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The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
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Paragraph 0251; 0252
(2020/02/18)
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- Method for synthesizing chiral 4-(N-carbobenzoxy) pyrrolidone
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The invention provides a method for synthesizing chiral 4-(N-carbobenzoxy) pyrrolidone. L-asparaginate is adopted as an initial raw material, through four steps of reactions of amino protection, diazo-reactions, carbonyl reduction and cyclization, chiral 4-(N-carbobenzoxy) pyrrolidone is prepared, raw materials are low in price and easy to obtain, chiral resolution is not needed in the reaction process, the yield is high, the reaction speed is rapid, a small amount of byproducts are generated, and the method is very applicable to industrial application.
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Paragraph 0021-0024
(2019/10/01)
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- Phosphate bioisostere containing amphiphiles: A novel class of squaramide-based lipids
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We describe a novel class of amphiphiles with squaramide moiety as a phosphate bioisostere. Most synthesized squaramide-based amphiphiles have the favorable physicochemical properties of lipids, such as: formation of stable liposomes or giant unilamellar vesicles in aqueous solution, high phase-transition temperature, low vesicle leakage and phospholipase resistance properties.
- Saha, Abhishek,Panda, Subhankar,Paul, Saurav,Manna, Debasis
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supporting information
p. 9438 - 9441
(2016/07/29)
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- Synthesis of a series of ω-dimethylaminoalkyl substituted ethylenediamine ligands for use in enantioselective catalysis
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The title compounds H2NCH((CH2)nNMe2)CH2NH2 L1-L4 (n = 1-4) are efficiently synthesized in enantiopure form. The commercial starting materials, l-asparagine, (S)-5-hydroxymethyl-2-pyrrolidinone, and (S)-6-(((benzyloxy)carbonyl)-amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid, are elaborated in 6-9 standard steps to give L1 (18% overall), L2 (13%), L3 (36%) and L4 (38%) or the corresponding tris(hydrochloric acid) salts [H3NCH((CH2)nNHMe2)CH2NH3]3+ 3Cl-, which are preferable for long term storage. The sequences make use of isobutyl carbamate, Cbz, and Boc protecting groups and Hofmann type rearrangements; the dimethylamino groups are introduced at late stages, either via reductive dimethylations or nucleophilic displacements involving mesylates and HNMe2. L1-L4 chelate to [Co(en)2]3+ fragments to give octahedral complexes that catalyze numerous enantioselective reactions.
- Ghosh, Subrata K.,Ganzmann, Carola,Gladysz, John A.
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p. 1273 - 1280
(2015/11/09)
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- Solution phase synthetic approach to fellutamide B
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Abstract A convenient solution phase approach for the synthesis of fellutamide B with efficient purification techniques has been demonstrated on the molecule for the first time. The strategy involves the use of natural amino acids as starting materials and classical peptide coupling reactions. The synthesis has been achieved in 10 steps with overall yield of 26.7% making the synthesis facile.
- Yadav, Jhillu Singh,Dachavaram, Soma Shekar,Grée, René,Das, Saibal
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supporting information
p. 3999 - 4001
(2015/06/08)
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- Total Synthesis of cis-Clavicipitic Acid from Asparagine via Ir-Catalyzed C-H bond Activation as a Key Step
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4-Substituted tryptophan derivatives and the total synthesis of cis-clavicipitic acid were achieved in reactions in which Ir-catalyzed C-H bond activation was a key step. The starting material for these reactions is asparagine, which is a cheap natural amino acid. The reductive amination step from the 4-substituted tryptophan derivative gave cis-clavicipitic acid with perfect diastereoselectivity.
- Tahara, Yu-Ki,Ito, Mamoru,Kanyiva, Kyalo Stephen,Shibata, Takanori
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p. 11340 - 11343
(2015/08/03)
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- Sulfate Encapsulation in Supramolecular Structures from L -Asparagine-Derived 2,5-Diketopiperazine Scaffolds: Anion Binding
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We report a new sulfate receptor, anchored onto 2,5-diketopiperazine units, which results in the formation of two types of supramolecules; one in which the sulfate ion guest fits snugly into extended cavities and the other in which the guest is sandwiched between layers. In each case, the anion is held by six hydrogen bonds from the host. 1H NMR spectroscopic solution studies enabled the construction of Job plots, and calculation of stoichiometry and association constants. These findings are of possible significance in drug design and for construction of combinatorial libraries.
- Naini, Santhosh Reddy,Lalancette, Roger A.,Gorlova, Olga,Ramakrishna, Kallaganti V. S.,Yadav, Jhillu Singh,Ranganathan, Subramania
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p. 7015 - 7022
(2016/02/19)
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- An improved large scale procedure for the preparation of N-Cbz amino acids
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A simple and scalable method for the preparation of N-Cbz protected amino acids is presented which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH during the addition of benzyl chloroformate. The method has been extended to other N-protections and is amenable to large scale preparation of an intermediate toward Zofenopril, an ACE inhibitor.
- Pehere, Ashok D.,Abell, Andrew D.
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experimental part
p. 1493 - 1494
(2011/05/16)
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- Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
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The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-XAA-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain.
- de Beer, Roseri J.A.C.,Zarzycka, Barbara,Amatdjais-Groenen, Helene I.V.,Jans, Sander C.B.,Nuijens, Timo,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 2201 - 2207
(2012/05/05)
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- Chemo-enzymatic preparation of chiral 3-aminopyrrolidine derivatives
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A new simple method for the enantioselective enzymatic hydrolysis of N-protected D-asparagine esters suitable for the use on the preparative scale is presented. Due to major obstacles observed under conventional reaction conditions - racemization of the retained ester and a strong enzyme inactivation - a comparatively low pH together with an organic co-solvent had to be employed. Under these conditions, nearly all tested proteases demonstrated good activity and excellent enantioselectivity giving access to the corresponding D-esters and L-asparagines in high optical purities (>95% ee) and good chemical yields (>40%). From the unnatural D-asparagine derivative, sequential cyclization, selective deprotection and reduction yielded efficiently benzyl protected (R)-3-aminopyrrolidine, a homo-chiral building block utilized in numerous drug candidates.
- Iding, Hans,Wirz, Beat,Rogers-Evans, Mark
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p. 647 - 653
(2007/10/03)
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- Utility of tetrathiomolybdate and tetraselenotungstate: Efficient synthesis of cystine, selenocystine, and their higher homologues
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Efficient synthesis of cystine, selenocystine, and their higher homologues like homo and bishomo amino acid derivatives from natural amino acid derivatives using tetrathiomolybdate and tetraselenotungstate reagents under mild and neutral conditions is reported. The generality of the reaction has been studied by capping various groups to amino and carboxyl components of canonical amino acids.
- Bhat, Ramakrishna G.,Porhiel, Emmanuel,Saravanan, Vadivelu,Chandrasekaran, Srinivasan
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p. 5251 - 5253
(2007/10/03)
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- Homochiral 4-azalysine building blocks: Syntheses and applications in solid-phase chemistry
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Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-Nα-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N2-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.
- Chhabra, Siri Ram,Mahajan, Anju,Chan, Weng C.
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p. 4017 - 4029
(2007/10/03)
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- TMS Triflate-Catalyzed Cleavage of Prenyl (3-Methylbut-2-enyl) Ester
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(Matrix Presented) Prenyl (3-methylbut-2-enyl) ester is catalytically cleaved by TMS triflate affording carboxylic acid and isoprene in high yield under mild conditions with high chemoselectivity without causing epimerization of the neighboring chiral cen
- Nishizawa, Mugio,Yamamoto, Hirofumi,Seo, Ken,Imagawa, Hiroshi,Sugihara, Takumichi
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p. 1947 - 1949
(2007/10/03)
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- Synthesis of alanine and proline amino acids with amino or guanidinium substitution on the side chain
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Competitive binding of peptides containing basic amino acids to disrupt or prevent the Tat-TAR interaction could result in diminished transcription as well as translation and hence constitutes an alternative way of controlling HIV replication. Therefore, we synthesized guanidinium and amino containing amino acids, based on a proline or an alanine scaffold. The introduction of the guanidinium moiety was best accomplished using 1H- pyrazole-1-carboxamidine hydrochloride, with Pmc used for its protection. The absence of racemization, maintained throughout the whole synthesis, was confirmed by chiral purity determination. These building blocks were smoothly incorporated into oligopeptides, which proved their suitability for use in a combinatorial approach for selecting TAR binding ligands. (C) 2000 Elsevier Science Ltd.
- Zhang, Zhenyu,Aerschot, Arthur Van,Hendrix, Chris,Busson, Roger,David, Frank,Sandra, Pat,Herdewijn, Piet
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p. 2513 - 2522
(2007/10/03)
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- Synthesis of (R)- and (S)-2,3-diaminopropyl sulfate: Mechanism based inhibition of glutamate 1-semialdehyde aminomutase
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A short synthesis of each enantiomer of 2,3-diaminopropyl hydrogensulfate is described starting from (2R)- and (2S)-asparagine. The compounds serve as inhibitors for pyridoxal 5'-phosphate-dependent (2S)- glutamate 1-semialdehyde aminotransferase, a target for selective herbicides and antibacterial agents on the tetrapyrrole biosynthetic pathway. The (2R)- enantiomer, as predicted, serves as a potent irreversible inactivator. (C) 2000 Elsevier Science Ltd.
- Khayer, Khurshida,Jenn, Thierry,Akhtar, Mahmoud,John, Robert,Gani, David
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p. 1637 - 1641
(2007/10/03)
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- Co-ordination chemistry of 3S-aminopyrrolidine and 3S-(methyl-amino)pyrrolidine: Crystallisation of the two diastereomers of dichloro[3S-(R,S-methylamino)pyrrolidine]palladium(II)
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Complexes of divalent Cu, Ni, Pd and Pt with 3S-aminopyrrolidine (S-ap) have been prepared and characterised by a combination of NMR, CD, electronic, IR and microanalytical techniques. The chosen chirality of the stereogenic carbon (S) forces the secondary nitrogen to adopt the R stereochemistry on co-ordination with the conformation of the 5-membered chelate being λ. The planar [M(S-ap)2]2+ complexes exist as a mixture of cis and trans isomers in the solid state and in solution. The trans arrangement is forced upon co-ordination of an axial donor (X = halide, thiocyanate or nitrite) in the five-co-ordinate ions [Cu(S-ap)2X]+. Methylation of the primary amine of S-ap generates another secondary nitrogen centre in the new ligand 3S-(methylamino)pyrrolidine, S-meap. This exocyclic nitrogen is not restricted to a single configuration on co-ordination. The complexes [M(S-meap)Cl2], where M = Pd or Pt, have been prepared and characterised. Both diastereoisomers (R- and S-NMe) of [Pd(S-meap)Cl2] crystallise from aqueous solution as distinct crystal forms which can be separated by mechanical means. The structure of the NMe(R) isomer has been determined by X-ray crystallography.
- Newman, Paul D.,Hursthouse, Michael B.,Malik, K. M. Abdul
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p. 599 - 606
(2007/10/03)
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- Regioselective reductions of various 3-aminosuccinimides; application to the synthesis of two heterocyclic systems
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The synthesis of novel pyrrolo[3,2-c]isoquinolines is investigated starting from 3-aminosuccinimides. Various known routes leading to 3-aminosuccinimides were tested but a new approach via nucleophilic addition of arylalkylamines on maleimide gave better results. The regioselectivity of the reduction of these compounds was shown to depend on the degree of substitution of the concerned 3-aminosuccinimide. The hydroxylactams are formed in-situ, then converted into the ethoxylactams. The latter, after generation of an iminium salt, afforded the target pyrroloisoquinolines and two further derivatives of another new heterocyclic system: the 3,6-methano-2,5-benzodiazocine.
- Briere, Jean-Francois,Charpentier, Patricia,Dupas, Georges,Queguiner, Guy,Bourguignon, Jean
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p. 2075 - 2086
(2007/10/03)
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- Synthesis of the HIV-proteinase inhibitor Saquinavir: A challenge for process research
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The task of process research, namely developing efficient, economically and technically as well as ecologically feasible syntheses in time, is demonstrated on the HIV-proteinase inhibitor Saquinavir (1), a complex molecule comprising six stereo-centres. Based on the first 26-step research synthesis furnishing a 10% overall yield, process research established a new, short 11-step synthesis affording a 50% overall yield.
- Goehring, Wolfgang,Gokhale, Surendra,Hilpert, Hans,Roessler, Felix,Schlageter, Markus,Vogt, Peter
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p. 532 - 537
(2007/10/03)
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- SYNTHESIS OF PYROGLUTAMYLASPARAGINE AMIDE DIPEPTIDE FRAGMENT OF VASOPRESSIN, AND THE STEREOSELECTIVITY OF ITS MNEMIC EFFECT
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Four diastereomers of pGlu-Asn-NH2 were synthesized.They were considered on one hand as a peptide analogue of piracetam, and on the other as an N-terminal fragment of the major metabolite of vasopressin 4, Cyt6>AVP(4-9).The influence of these diastereomers on the memory of rats was studied in the passive avoidance conditioned reflex test.It was shown that L-pGlu-L-Asn-NH2 and D-pGlu-D-Asn-NH2 in the same doses facilitate the training of rats; D-pGlu-D-Asn-NH2 is inactive, and L-pGlu-D-Asn-NH2 has amnestic activity.These facts suggest a receptor mechanism for the action of the dipeptide pGlu-Asn-NH2 and are the basis for a hypothesis for the topology of the nootropic receptor binding site.
- Gudasheva, T. A.,Rozantsev, G. G.,Ostrovskaya, R. U.,Trofimov, S. S.,Voronina, T. A.,et al.
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- Improved efficiency and selectivity in peptide synthesis: Use of triethylsilane as a carbocation scavenger in deprotection of t-butyl esters and t-butoxycarbonyl-protected sites
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The use of triethylsilane as a carbocation scavenger in the presence of trifluoroacetic acid in dichloromethane leads to increased yields, decreased reaction times, simple work-up and improved selectivity for the deprotection of t-butyl ester and t-butoxycarbonyl sites in protected amino-acids and peptides in the presence of other acid-sensitive protecting groups such as the benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, O- and S-benzyl and t-butylthio groups.
- Mehta, Anita,Jaouhari, Rabih,Benson, Timothy J.,Douglas, Kenneth T.
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p. 5441 - 5444
(2007/10/02)
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- Direct Optical Resolution of Carboxylic Acids by Chyral HPLC on Tris(3,5-dimethylphenylcarbamate)s of Cellulose and Amylose
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A variety of racemic carboxylic acids have been for the first time directly resolved by normal-phase, high-performance liquid chromatography using a hexane-2-propanol eluting system containing a small amount (ca. 1percent) of a strong carboxylic acid, like formic acid, trichloroacetic acid, and trifluoroacetic acid.
- Okamoto, Yoshio,Aburatani, Ryo,Kaida, Yuriko,Hatada, Koichi
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p. 1125 - 1128
(2007/10/02)
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