- Synthesis of orthogonally protected L-homocysteine and L-2-amino-4-phophonobutanoic acid from L-homoserine
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Convenient syntheses of N-tert-butoxycarbonyl-S-p-methoxybenzyl-L-homocysteine benzyl ester and benzyl L-4-dimethylphosphono-2-N-phthalimidobutanoate from commercially available L-homoserine are described along with their incorporation into dipeptides.
- Nair,Lee,Hangauer
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- Synthesis of sunitinib-metastin conjugate, a novel esterase-sensitive prodrug system based on lactonization reaction
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We describe a strategy for preparing sunitinib-metastin conjugate, a prodrug composed of the anticancer agent sunitinib for renal cell carcinoma and the carrier protein metastin, which are conjugated to each other by a linker. We designed a modified L-homoserine linker, which is composed of an acyl group that acts as the masking group for hydrolysis with an esterase, as well as a carbon chain of appropriate length between sunitinib and metastin. The sunitinib-metastin conjugate was converted into a hydrolyte by hydrolysis of the acyl group with an esterase, and sunitinib was released by intramolecular lactonization. Sunitinib-metastin conjugate, an esterase-sensitive amide prodrug that has a modified L-homoserine linker that participates in the intramolecular lactonization, was synthesized.
- Takahashi, Yuki,Shoji, Sunao,Morishige, Takuya,Katsumata, Aya,Tsurifune, Fumihiro,Tsutsumi, Mitsuhiro,Honda, Yoshiharu,Hasuda, Tomoyo,Hitotsuyanagi, Yukio,Terachi, Toshiro,Uchida, Toyoaki,Takeya, Koichi
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- Light Harvesting for Rapid and Selective Reactions: Click Chemistry with Strain-Loadable Alkenes
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Intramolecular strain is a powerful driving force for rapid and selective chemical reactions, and it is the cornerstone of strain-induced bioconjugation. However, the use of molecules with built-in strain is often complicated as a result of instability or selectivity issues. Here, we show that such strain, and subsequent cycloadditions, can be mediated by visible light via the harvesting of photochemical energy. Through theoretical investigations and molecular engineering of strain-loadable cycloalkenes, we demonstrate the rapid chemoselective cycloaddition of alkyl azides with unstrained cycloalkenes via the transiently (reversibly) formed trans-cycloalkene. We assess this system via the rapid bioconjugation of azide-functionalized insulin. An attractive feature of this process is the cleavable nature of the linker, which makes a catch-and-release strategy possible. In broader terms, we show that conversion of photochemical energy to intramolecular ring strain is a powerful strategy that can facilitate complex chemical transformations, even in biomolecular systems. Probing, isolating, and/or manipulating biologically relevant macromolecules is central to the study of their function in living systems. However, the synthetic tools available for performing the chemistry necessary for such studies are often difficult to use or limited in utility. In the approach presented here, light is converted to molecular strain energy, which can in turn be used for performing rapid and highly selective chemistry on macromolecular systems. Because it involves chemically stable and chemoselective reactions, this research not only opens up new possibilities for biomolecular functionalization and manipulation but also promises to make such experiments accessible to a broader class of researchers. The central concept of strain-loadable alkenes is general and provides a firm foundation for light-activated chemistry in complex environments. Strain-loadable alkenes are cycloalkenes that, when irradiated in the presence of a visible-light-absorbing photocatalyst, undergo double-bond isomerization. Because of engineered geometrical constraints, this isomerization results in significant molecular strain. Weaver and colleagues exploit this strain to dramatically accelerate the cycloaddition with azides, which are otherwise unreactive, in mixed molecular environments.
- Singh, Kamaljeet,Fennell, Christopher J.,Coutsias, Evangelos A.,Latifi, Reza,Hartson, Steve,Weaver, Jimmie D.
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- Peptide analogues of DNA consisting of L-α-amino-γ-thymine butyric acid and L-valine subunits
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Reaction of N-Boc-L-homoserine benzylester with N3-benzoylthymine under Mitsunobu conditions afforded N-Boc-L-α-amino-γ-N3-benzoylthymine butyric acid benzylester. After removal of the N-benzoyl and O-benzyl protecting group, this compound was used in solution phase peptide synthesis.
- Ceulemans,Khan,Van Schepdael,Herdewijn
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- NOVEL HISTONE METHYLTRANSFERASE INHIBITORS
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The present invention relates to novel compounds of formula (I) as defined herein. The compounds are inhibitors of histone methyltransferases of the seven-beta-strand family, in particular of KMT9.
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- Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure
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Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 β-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1′ position further improved the activity.
- Otani, Takuya,Hattori, Yasunao,Akaji, Kenichi,Kobayashi, Kazuya
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- Method for synthesizing L- cystathionine hydrochloride (by machine translation)
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The invention relates to a synthetic method of L - cystathionine hydrochloride. The method mainly solves the technical problems of potential safety hazards and difficulty in purification in the existing synthetic method. To L - homoserine which can be lar
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- CYCLIC PEPTIDE ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00208
(2020/09/27)
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- Design and Optimization of an Acyclic Amine Series of TRPV4 Antagonists by Electronic Modulation of Hydrogen Bond Interactions
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Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopp
- Patterson, Jaclyn R.,Terrell, Lamont R.,Donatelli, Carla A.,Holt, Dennis A.,Jolivette, Larry J.,Rivero, Ralph A.,Roethke, Theresa J.,Shu, Arthur,Stoy, Patrick,Ye, Guosen,Youngman, Mark,Lawhorn, Brian G.
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- 2,4-diaminobutyric acid derivative and preparation method thereof
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The invention relates to a 2,4-diaminobutyric acid derivative and a preparation method thereof and relates to the field of medicine synthesis. An aspartic acid derivative serves as an initiator, and the 2,4-diaminobutyric acid derivative is obtained through simple reduction and substitution reaction. Different from the prior art, a reagent adopted for the method is small in toxicity, reaction conditions are mild, requirements for a device are not high, synthesis steps are simple, the 2,4-diaminobutyric acid derivative can be obtained at a high total yield, and the 2,4-diaminobutyric acid derivative facilitates large-scale industrial production and can be well applied to medicine synthesis.
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Paragraph 0038; 0039; 0040
(2017/07/20)
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- STEREOSELECTIVE SYNTHESIS OF CIS-4-METHYLSPHINGOSINE AND DERIVATIVES THEREOF
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The invention provides for synthesis of a (S-R) dihydroxy-amino-methylalkylene characterized by the general formula I, or its R-S diastereomer, wherein R1 is CH2OH or CH2-CH2OH, and R2 is C2 to C20 al
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Page/Page column 16-17
(2012/11/14)
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- Stereoselective Synthesis of cis-4-Methylsphingosin
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The invention provides for synthesis of a (S-R) dihydroxy-amino-methylalkylene characterized by the general formula I, or its R-S diastereomer, wherein R1 is CH2OH or CH2-CH2OH, and R2 is C2 to C20 alkyl, whereby a compound characterized by the general formula II, with R3, R4 and R5 being protecting groups for amino and hydroxyl functions, respectively, is used as a starting material. The invention further provides novel intermediates for syntheses of, and analogues to, cis-4-methylsphingosine.
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Page/Page column 10
(2012/12/13)
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- Efficient synthesis of benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-ω- iodoalkanoates
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The efficient synthesis of four benzyl 2-(S)-[(tert-butoxycarbonyl)amino]- ω-iodoalkanoates {benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-3- iodopropanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-4-iodobutanoate, benzyl 2-(S)-[(tert-butoxycarbonyl)amino]-
- Koseki, Yohei,Yamada, Haruka,Usuki, Toyonobu
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experimental part
p. 580 - 586
(2011/06/21)
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- A concise route to L-azidoamino acids: L-azidoalanine, L-azidohomo-alanine and L-azidonorvaline
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A simple and highly efficient synthetic route to three homologous azidoamino acids, starting from inexpensive, commercially available, protected natural amino acids is reported. The products can be used to introduce bioorthogonal handles into proteins. Ge
- Roth, Stefanie,Thomas, Neil R.
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scheme or table
p. 607 - 609
(2010/09/18)
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- Potent and fully noncompetitive peptidomimetic inhibitor of multidrug resistance P-glycoprotein
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Nα-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-proline (4(R)Hyp) gave compounds 11 and 15 characterized by half-maximal inhibitory concentrations (IC50) of 0.6 and 0.2 μM, which are 2-and 7-fold lower than that of the parent molecule. The difference in IC50 between 11 and 15 rests on the carbonyl group of the peptidyl bond, reduced in 15. Those compounds are rather specific of P-gp, having no or limited activity on MRP1 and BCRP. 15 displayed no marked cytotoxicity up to 10-fold its IC50. Importantly, 15 equally inhibited the Hoechst 33342 and daunorubicin effluxes through a typical noncompetitive inhibition mechanism, suggesting its binding to a site different from the H and R drug-transport sites.
- Arnaud, Ophélie,Koubeissi, Ali,Ettouati, Laurent,Terreux, Rapha?l,Alamé, Ghina,Grenot, Catherine,Dumontet, Charles,Di Pietro, Attilio,Paris, Jo?lle,Falson, Pierre
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supporting information; experimental part
p. 6720 - 6729
(2010/11/16)
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- AMINO- AND AMIDO-AMINOTETRALIN DERIVATIVES AND RELATED COMPOUNDS AS MU OPIOID RECEPTOR ANTAGONISTS
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The invention provides amino- and amido-aminotetralin compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, and n are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
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(2009/10/06)
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- Identification of stable S-adenosylmethionine (SAM) analogues derivatised with bioorthogonal tags: Effect of ligands on the affinity of the E. coli methionine repressor, MetJ, for its operator DNA
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The efficient synthesis of a range of stable SAM mimetics, and their ability to promote the binding of the E. coli methionine repressor (MetJ) to its operator DNA, is described.
- Joce, Catherine,Caryl, Jamie,Stockley, Peter G.,Warriner, Stuart,Nelson, Adam
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supporting information; experimental part
p. 635 - 638
(2009/06/19)
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- Novel acyl-dipeptide-like compounds bearing an accessory functional side chain spacer, a method for preparing the same and pharmaceutical compositions containing such products
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The present invention is directed in particular to dipeptide-like compounds derived from functionally substituted amino acids, having fatty acid chains bound thereto through amidification of the amine functional groups of said dipeptide-like compounds, one end portion of which bears an accessory functional side chain spacer, with the other end portion being an acid group either in neutral or charged state. Compounds of the present invention have immunomodulating properties like adjuvants, In addition, compounds of the invention can be grafted on a given antigen in order to modulate or tune the immune response or can be equally grafted on a pharmaceutical carrier to enhance the therapeutic effect or targetting thereof. Accordingly, compounds of the invention find use in human and veterinary medicine both as immunogens and diagnostic tools.
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- Synthesis of a cyclen-functionalized α-amino acid and its incorporation into peptide sequence
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A cyclen-functionlized α-amino acid was obtained through embedding cyclen into the side chain of homoserine. The α-amino acid can be conveniently incorporated into peptide sequence to form new ligands, which have strong coordination ability for transition metal ions. Georg Thieme Verlag Stuttgart.
- Chen, Shan-Yong,Huang, Yu,Zhang, Guo-Lin,Cheng, Hua,Xia, Chuan-Qin,Ma, Li-Jian,Yu, Hong,Yu, Xiao-Qi
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p. 888 - 892
(2007/10/03)
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- A general strategy for the synthesis of azapeptidomimetic lactams
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A selection of azapeptidomimetics containing constraining lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives. These include sterically-congested β-lactams, as well as γ-butyrolactam and δ-valerolac
- Broadrup, Robert L.,Wang, Bei,Malachowski, William P.
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p. 10277 - 10284
(2007/10/03)
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- SUBSTITUTED QUINOLINE CCR5 RECEPTOR ANTAGONISTS
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The present invention relates to CCR5 receptor antagonists of formulae (1a) or (1b), enantiomers, diastereomers, salts and solvates thereof wherein R1, R2, R3, R4, R5, and R7 are as defined herein. The invention further includes a method of CCR5-mediated
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(2010/02/06)
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- NOVEL GAMMA-LACTAMS AS BETA-SECRETASE INHIBITORS
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There is provided a series of novel substituted gamma-lactams of Formula (I) wherein R1, R2, R3, R4 and R5 are defined herein, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of aβ-peptide. The present invention is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
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(2008/06/13)
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- Acyl pseudodipeptides which carry a functionalised auxialiary arm
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The present invention is directed in particular to dipeptide-like compounds derived from functionally substituted amino acids, having fatty acid chains bound thereto through amidification of the amine functional groups of said dipeptide-like compounds, one end portion of which bears an accessory functional side chain spacer, with the other end portion being an acid group either in neutral or charged state. Compounds of the present invention have immunomodulating properties like adjuvants, In addition, compounds of the invention can be grafted on a given antigen in order to modulate or tune the immune response or can be equally grafted on a pharmaceutical carrier to enhance the therapeutic effect or targetting thereof. Accordingly, compounds of the invention find use in human and veterinary medicine both as immunogens and diagnostic tools.
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- A novel dipeptide, N-γ-glutamyl boletine, and a cyclic iminium toxin from the mushroom Tylopilus sp. (Boletaceae)
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N-γ-Glutamyl boletine and a toxin, 2-butyl-1-azacyclohexene iminium salt, were isolated from the mushroom Tylopilus sp. (Boltaceae). The absolute stereostructure of N-γ-glutamyl boletine was clarified based on spectroscopic analysis, acidic hydrolysis and total synthesis. N-γ-Glutamyl boletine exhibited moderate antibacterial activity. 2-Butyl-1-azacyclohexene iminium salt exhibited moderate acute toxicity against ddY mice. We proposed feasible biosynthetic pathway of piperidine alkaloids that the cyclic iminium compound might be biosynthesized from boletine, a new amino acid containing an δ-amino ketone moiety.
- Watanabe, Reiko,Kita, Masaki,Uemura, Daisuke
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p. 6501 - 6504
(2007/10/03)
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- Concise Synthesis of Enantiomerically Pure Phenylalanine, Homophenylalanine, and Bishomophenylalanine Derivatives Using Organozinc Chemistry: NMR Studies of Amino Acid-Derived Organozinc Reagents
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Protected phenylalanines 23 (seven examples), homophenylalanines 7 (eight examples), and bishomophenylalanines 8 (seven examples) have been prepared by palladium-catalyzed coupling of the amino acid-derived organozinc reagents 13, 5, and 6, respectively, with aryl iodides. While the reactions of the zinc reagent 13 may be conducted in both THF and DMF as solvent, the results obtained in DMF are generally superior. In the case of the reagents 5 and 6 the results are far superior in DMF. NMR investigations on the structure of the zinc reagents 13 in THF suggest that there is strong intramolecular coordination of the urethane carbonyl group, whereas in DMF this interaction is completely suppressed.
- Jackson, Richard F. W.,Moore, Rebecca J.,Dexter, Charles S.,Elliott, Jason,Mowbray, Charles E.
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p. 7875 - 7884
(2007/10/03)
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- Total syntheses of phytosiderophores, 3-epi-hydroxymugineic acid, distichonic acid A, and 2'-hydroxynicotianamine
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First total syntheses of unique phytosiderophores, 3-epi-hydroxymugineic acid (2), distichonic acid A (3), and 2'-hydroxynicotianamine (5), have been efficiently achieved from the same intermediates used for the synthesis of mugineic acid (1), the typical phytosiderophore.
- Matsuura,Hamada,Shioiri
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p. 265 - 274
(2007/10/02)
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- N-ACYLAMINO ACID DERIVATIVES AND THEIR PHARMACEUTICAL COMPOSITIONS
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An N-acylamino acid derivative of the formula: STR1 wherein the substituents are herein defined or a salt thereof, which is useful as hypotensive drugs.
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- A facile synthesis of chiral N-protected β-amino alcohols
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Chiral N-protected β-amino alcohols are easily obtained by NaBH4 reduction of mixed anhydrides of N-protected α-amino acids in an organic/aqueous medium. The alcohols obtained from side chain or main chain reduction of N-protected aspartic acid are converted in good yields into lactones.
- Rodriguez,Llinares,Doulut,Heitz,Martinez
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p. 923 - 926
(2007/10/02)
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