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Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine
Three human G protein-coupled receptors (GPCRs)—GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3—are activated specifically by lysophosphatidylserine (LysoPS), an endogenous hydrolysis product of a cell membrane component, phosphatidylserine (PS). LysoPS consists of-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages. We previously generated potent and selective GPCR agonists by modification of the three modules and the ester linkage. Here, we show that a novel modification of the hydrophilic serine moiety, that is, N-acylations of the serine amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural exploration of the amide functionality provided access to a range of activities from agonist to partial agonist to antagonist. The present study would provide a new strategy for the development of lysophospholipid receptor antagonists.
Sayama, Misa,Uwamizu, Akiharu,Ikubo, Masaya,Chen, Luying,Yan, Ge,Otani, Yuko,Inoue, Asuka,Aoki, Junken,Ohwada, Tomohiko
p. 10059 - 10101
(2021/07/28)

Practical Cleavage of Acetals by Using an Odorless Thiol Immobilized on Silica
A practical, efficient and general method was developed for the deprotection of a variety of aromatic and aliphatic acetals to their corresponding catechol or diol derivatives using thiol immobilized on silica gel. This is an application for the well-known commercial solid-supported thiol (SiliaMetS Thiol). The procedure is mild and amenable to scale-up. It does not require inert atmosphere and clean conversions were observed. This method is applicable to substituted 1,3-benzodioxole and aliphatic acetals with different functionalities. It offers the advantage of a general route with high yield, which can be undertaken at ambient temperature.
de Léséleuc, Mylène,Kukor, Andrew,Abbott, Shaun D.,Zacharie, Boulos
p. 7389 - 7393
(2019/12/03)

Toward aplyronine payloads for antibody-drug conjugates: Total synthesis of aplyronines A and D
The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.
An?i?ek, Nika,Williams, Simon,Housden, Michael P.,Paterson, Ian
supporting information
p. 1343 - 1350
(2018/03/06)

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers
The proposed diastereoisomers (1 a–d) together with their C8′-epimers (1 e–h) of amipurimycin, a unique antifungal peptidyl nucleoside antibiotic, have been synthesized for the first time. The synthetic approach is efficient and stereodivergent, and features a stereoselective aldol condensation to build the branched C9 sugar amino acid skeleton and a regio- and stereocontrolled gold(I)-catalyzed N-glycosylation to furnish the purine nucleoside. Analysis of the NMR data suggests that the previously assigned configuration of the tertiary C3′ in amipurimycin should be of opposite configuration.
Wang, Shengyang,Sun, Jiansong,Zhang, Qingju,Cao, Xin,Zhao, Yachen,Tang, Gongli,Yu, Biao
supporting information
p. 2884 - 2888
(2018/02/16)

An efficient and facile synthesis of D-cycloserine substantially free from potential impurities
An efficient and facile synthesis of D-cycloserine has been developed from D-serine with 61% overall yield employing protectiondeprotection strategy. Different parameters affecting the impurities content and yield of D-cycloserine have been studied. Mild reaction conditions provided the product with remarkable purity (>99%) and high stability.
Awasthi, Arun Kumar,Kumar, Brijesh,Aga, Mushtaq A,Tripathi, Punit,Reddy, Cirandur Suresh,Kumar, Pramod
p. 1248 - 1253
(2018/02/14)

Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation of Peptides
A mild and effective method is described for 11C-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium–methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [11C]carbon monoxide. The protocol facilitates the production of native N-11C-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.
Andersen, Thomas L.,Nordeman, Patrik,Christoffersen, Heidi F.,Audrain, Hélène,Antoni, Gunnar,Skrydstrup, Troels
supporting information
p. 4549 - 4553
(2017/04/13)

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES
Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme
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Paragraph 000166

(2016/09/26)

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES
Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
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Paragraph 000219

(2015/04/15)

N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE DERIVATIVES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and compounds I for use to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
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Paragraph 000201

(2015/05/19)

Lewis acid facilitated regioselective synthesis of τ-histidinoalanine
τ-Histidinoalanine, with an unusual cross-link between His and Ala, is the central component of theonellamides, a family of bioactive peptidic natural products. Previous syntheses of this residue were plagued with low regioselectivity in the alkylation step. Herein, we report two novel routes to τ-histidinoalanine, involving alkylation of Boc-His-OMe with a serine-derived β-lactone and β-bromoalanine, respectively, as the electrophiles. The use of Mg(OTf)2 as a catalyst was found to be essential to ensure high regioselectivity for the τ-isomer, presumably due to the formation of a six-membered ring chelation involving the π-nitrogen atom of histidine.
Wu, Ju,Ma, Bing,Wang, Yuehui,Zhang, Yue,Yan, Shenghu,Castle, Steven L.
p. 3114 - 3116
(2014/05/20)

Polyhydroxylated pyrrolidine and 2-oxapyrrolizidine as glycosidase inhibitors
Using D-serine as a chiral precursor, a polyhydroxylated pyrrolidine (1), its derivatives bearing carboxylate, phosphate and phosphonate groups (2-4) and an oxapyrrolizidine (5) were synthesized. The pyrrolidine ring was formed by intramolecular amino-mercuration. The bicyclic scaffold of oxapyrrolizidine was further constructed by an intramolecular attack of the carbamate group on the iodomethyl group. Compounds 1 and 5 were found to inhibit β-glucosidase and α-galactosidase, respectively, in a competitive manner, whereas compounds 2, 3 and 4 did not produce significant inhibition against glycosidases. The Royal Society of Chemistry 2013.
Wang, Jen-Tsung,Lin, Ting-Chien,Chen, Ying-Hsuan,Lin, Chun-Hung,Fang, Jim-Min
p. 783 - 791
(2013/08/26)

N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships
The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
Duranti, Andrea,Tontini, Andrea,Antonietti, Francesca,Vacondio, Federica,Fioni, Alessandro,Silva, Claudia,Lodola, Alessio,Rivara, Silvia,Solorzano, Carlos,Piomelli, Daniele,Tarzia, Giorgio,Mor, Marco
scheme or table
p. 4824 - 4836
(2012/07/03)

One-pot preparation of 3-hydroxymethyl 2,5-diketopiperazine for total synthesis of peticinnamin E
3-Hydroxymethyl 2, 5-diketopiperazine is a structure unit of pepticinnamin E, a natural product and a bi-substrate inhibitor of FPTase. In this paper, a facile synthetic strategy was developed to prepare 3-hydroxymethyl 2, 5-diketopiperazine with high yie
Sun, Dequn,Sun, Li,Luo, Min,Gou, Zhaopin
experimental part
p. 5169 - 5170
(2012/06/18)

Primary amino acid derivatives: Compounds with anticonvulsant and neuropathic pain protection activities
Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.
King, Amber M.,Salomé, Christophe,Dinsmore, Jason,Salomé-Grosjean, Elise,De Ryck, Marc,Kaminski, Rafal,Valade, Anne,Kohn, Harold
supporting information; experimental part
p. 4815 - 4830
(2011/10/01)

PROCESS FOR PREPARING (R)-2-ACETAMIDO-N-BENZYL-3-METHOXY-PROPIONAMIDE
Processes for preparing and purifying (R)-2-acetamido-N-benzyl-3-methoxy- propionamide of formula-1 and intermediates thereof are provided.
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Page/Page column 37-38

(2011/09/15)

Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters, and ethers
(Chemical Equation Presented) Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative 4, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.
Li, Bryan,Berliner, Martin,Buzon, Richard,Chiu, Charles K.-F.,Colgan, Stephen T.,Kaneko, Takushi,Keene, Nandell,Kissel, William,Le, Tung,Leeman, Kyle R.,Marquez, Brian,Morris, Ronald,Newell, Lisa,Wunderwald, Silke,Witt, Michael,Weaver, John,Zhang, Zhijun,Zhang, Zhongli
p. 9045 - 9050
(2007/10/03)

Serine and threonine β-lactones: A new class of hepatitis A virus 3C cysteine proteinase inhibitors
Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and infectivity and represents a target for the development of antiviral drugs. A number of serine and threonine β-lactones were synthesized and tested against HAV 3C proteinase. The D-N-Cbz-serine β-lactone 5a displays competitive reversible inhibition with a Ki value of 1.50 × 10-6 M. Its enantiomer, L-N-Cbz-serine β-lactone 5b is an irreversible inactivator with kinact = 0.70 min-1, KI = 1.84 × 10-4 M and kinact/KI = 3800 M-1 min-1. Mass spectrometry and HMQC NMR studies using 13C-labeled 5b show that inactivation of the enzyme occurs by nucleophilic attack of the cysteine thiol (Cys-172) at the β-position of the oxetanone ring. Although the N-Cbz-serine β-lactones 5a and 5b display potent inhibition, other related analogues with an N-Cbz side chain, such as the five-membered ring homoserine γ-lactones 14a and 14b, the four-membered ring β-lactam 33, 2-methylene oxetane 34, cyclobutanone 36, and 3-azetidinone 39, fail to give significant inhibition of HAV 3C proteinase, thus demonstrating the importance of the β-lactone ring for binding.
Lall, Manjinder S.,Ramtohul, Yeeman K.,James, Michael N.G.,Vederas, John C.
p. 1536 - 1547
(2007/10/03)

A practical route to regiospecifically substituted (R)- and (S)-oxazolylphenols
New, diversely substituted phenolic oxazolines 14a-d and 15a-d were prepared by two complementary routes A and B, starting from salicylic derivatives 4-7 and various enantiomerically pure 1,2-amino alcohols 13a-d. In route A, the 1,2amino alcohols 13a-d were directly condensed with the salicylic acids 5 and 7, using the Appel reaction, whereas in route B the amino alcohols 13b-d were treated with the 2-hydroxybenzonitriles 4 and 6, under Witte-Seeliger conditions. The latter route was advantageous for L-valinol 13b and L-tert-leucinol 13c, while route A was the method of choice for the new, sterically demanding amino alcohol 13a, prepared from D- and L-serine. The nitro group in the salicylic derivatives 5 and 6 was introduced by means of a regiospecific ipso substitution of a tert-butyl group by nitric acid. The structure of the nitro product 5 was unambiguously assigned by NOE spectroscopy on the basis of the recently developed DPFGSE-ROE pulse sequence.
Scheurer, Andreas,Mosset, Paul,Bauer, Walter,Saalfrank, Rolf W.
p. 3067 - 3074
(2007/10/03)

A New Highly Chemo- and Regioselective Alkoxycarbonylation of Amino Alcohols and Polyols
The alkoxycarbonylating carbamates 1 and 2 are readily prepared and reacted under mild conditions with polyfunctional substrates, e.g. amino acids, unsymmetrical diols, and unprotected carbohydrates (D-glucosamine and methyl α-D-glucoside), thus affording carbamates or monocarbonates in good yields and with high chemo- and regioselectivity.
Allainmat, Monique,L'Haridon, Paul,Toupet, Loic,Plusquellec, Daniel
p. 27 - 32
(2007/10/02)

Direct Optical Resolution of Carboxylic Acids by Chyral HPLC on Tris(3,5-dimethylphenylcarbamate)s of Cellulose and Amylose
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
p. 1125 - 1128
(2007/10/02)

PAPAIN-ASSISTED RESOLUTION OF NATURAL AND XENOBIOTIC α-AMINO ACIDS
A new and convenient method for the preparation of pure enantiomers of α-amino acids is described.Industrial papain, catalyzes the synthesis of L-Z-amino acid ethyl esters in ethanolic medium, with good yields.These esters are obtained from DL-Z-amino acids with 100percent optical purity.Unreactive D-Z-amino acids are readily isolated from reaction medium.Physical constants of natural and xenobiotic L-Z-amino acid esters and D-Z-amino acids are described.
Moriniere, J. L.,Danree, B.,Lemoine, J.,Guy, A.
p. 441 - 444
(2007/10/02)

Synthesis of α-Carbalkoxy Enethiols: A Class of Tautomeric Thiopyruvate Derivatives. Application to Griseoviridin
A general approach to previously inaccessible α-carbalkoxy enethiols 1 is described (e.g., 4 -> 5 -> 6 -> 7), and the use of such substances in synthesis is illustrated (11).
Butera, John,Rini, Josephine,Helquist, Paul
p. 3676 - 3678
(2007/10/02)