- Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks
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Diastereoselective fluorination of N-Boc (R)- and (S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure (S,S)- and (R,S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.
- Wei, Wei,Khangarot, Rama Kanwar,Stahl, Lothar,Veresmortean, Cristina,Pradhan, Padmanava,Yang, Lijia,Zajc, Barbara
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- Total Synthesis of the Post-translationally Modified Polyazole Peptide Antibiotic Goadsporin
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The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is repo
- Dexter, Hannah L.,Williams, Huw E. L.,Lewis, William,Moody, Christopher J.
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- Synthesis of D-erythro-sphingosine and D-erythro sphinganine via 3- ketosphinganine
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D-erythro- sphingosine and D-erythro-sphinganine can be produced in protected form from serine by a synthetic approach in which the normal biological intermediate 3-ketosphinganine in protectyed form, is a key synthetic intermediate. The sequence is short and convergent, proceeds in good overall yields (? 30% for 6 steps) and with excellent stereocontrol (>91% de, >95% ee).
- Hoffman, Robert V.,Tao, Junhua
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- A Straightforward Synthesis of Allyl Amines from α-Amino Acids without Racemization
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An extremely simple and practical synthesis of allyl amine derivatives from α-amino acids has been developed involving aldehyde olefination pathway with AlMe3-Zn-CH2I2 reagent which has proven to be crucial for preservation of stereochemical integrity.
- Moriwake, Toshio,Hamano, Shin-ichi,Saito, Seiki,Torii, Sigeru
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- A straightforward synthesis of N-tert-butoxycarbonyl serinate acetonide methyl ester
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N-tert-Butoxycarbonyl serinate acetonide methyl ester, an important intermediate in organic synthesis, can be obtained in large quantity according to the procedure described herein.
- Branquet,Durand,Vo-Quang,Le Goffic
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- Mild and facile procedure for clay-catalyzed acetonide protection and deprotection of N(Boc)-amino alcohols and protection of 1,2-diols
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The application of clay as a catalyst for acetonide protection of N(Boc)-amino alcohols and 1,2-diols to obtain good to excellent yields of the acetonide derivatives is described. Acetonide deprotection to obtain the parent amino alcohol was carried out using a similar catalyst in the presence of methanol as solvent. The reaction takes place at room temperature within 2h to give the parent amino alcohol in quantitative yield keeping the N(Boc) group intact.
- Shaikh, Nadim S.,Bhor, Santosh S.,Gajare, Anil S.,Deshpande, Vishnu H.,Wakharkar, Radhika D.
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- Ceramides: Branched alkyl chains in the sphingolipid siblings of diacylglycerol improve biological potency
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The synthesis of a small number of ceramide analogues containing a combination of linear and highly branched alkyl chains on either the d-sphingosine or the N-acyl core of the molecule is reported. Regardless of location, the presence of the branched chain improves potency relative to the positive control, C2 ceramide; however, the most potent compound (4) has the branched side chain as part of the d-sphingosine core. The induction of apoptosis by 4 in terms of Annexin V binding and DiOC6 labeling was superior to that achieved with C2 ceramide.
- Kang, Ji-Hye,Garg, Himanshu,Sigano, Dina M.,Francella, Nicholas,Blumenthal, Robert,Marquez, Victor E.
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- Synthesis of Nontoxic Fluorous Sphingolipids as Molecular Probes of Exogenous Metabolic Studies for Rapid Enrichment by Fluorous Solid Phase Extraction
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Fluorous solid-phase extraction (FSPE) is a useful technique for efficient selective enrichment of fluorous compounds from nonfluorous molecules. Sphingolipids and their metabolites, which are ubiquitous building blocks of eukaryotic and prokaryotic cell membranes, play crucial roles, for example, as signaling molecules. However, details of the functions and metabolic mechanisms of exogenous sphingolipids have remained unknown compared with those of their endogenous analogs. To better understand these unknown roles, chemical probes with appropriate biological and physicochemical properties are needed. In this study, we designed and synthesized new fluorous sphingolipids to reveal these roles. Furthermore, we confirmed that they could be efficiently and rapidly separated from normal sphingolipids by FSPE, and that they hardly showed any cytotoxic activity, similarly to normal sphingolipids at the same dose. We also showed that these fluorinated ceramides could act as metabolic substrates for sphingomyelin synthase 2 (SMS2). This demonstrates their potential for further biological studies.
- Saito, Shota,Murai, Yuta,Usuki, Seigo,Yoshida, Masafumi,Hammam, Mostafa A. S.,Mitsutake, Susumu,Yuyama, Kohei,Igarashi, Yasuyuki,Monde, Kenji
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- Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate
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A solution-phase automated synthesis of the versatile synthetic intermediate, Garner's aldehyde, was demonstrated. tert-Butoxycarbonyl (Boc) protection, acetal formation, and reduction of the ester to the corresponding aldehyde were performed utilizing our originally developed automated synthesizer, ChemKonzert. The developed procedure was also useful for the synthesis of Garner's aldehyde analogues possessing fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection.
- Masui, Hisashi,Yosugi, Sae,Fuse, Shinichiro,Takahashi, Takashi
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- Alcohol functionality in the fatty acid backbone of sphingomyelin guides the inhibition of blood coagulation
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Cell-surface sphingomyelin (SM) inhibits binary and ternary complex activity of blood coagulation by an unknown mechanism. Here we show the OH functionality of SM contributes in forming the close assembly through intermolecular H-bond and through Ca2+ chelation, which restricts the protein-lipid/protein-protein interactions and thus inhibits the coagulation procedure.
- Mallik,Prasad,Das,Sen
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- Chemoenzymatic Total Synthesis of GM3 Gangliosides Containing Different Sialic Acid Forms and Various Fatty Acyl Chains
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Gangliosides are sialic acid-containing glycosphingolipids that have been found in the cell membranes of all vertebrates. Their important biological functions are contributed by both the glycan and the ceramide lipid components. GM3 is a major ganglioside
- Yu, Hai,Gadi, Madhusudhan Reddy,Bai, Yuanyuan,Zhang, Libo,Li, Lei,Yin, Jun,Wang, Peng G.,Chen, Xi
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- Telomestatin: Formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes
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The structurally unique natural product telomestatin incorporates seven oxazole rings and one sulfur-containing thiazoline in a macrocyclic arrangement. The compound is a potent inhibitor of the enzyme telomerase and therefore provides a structural framework for developing new potential therapeutic agents for cancer. An efficient formal total synthesis of telomestatin is reported in which the key steps are the use of dirhodium-(II)-catalyzed reactions of diazocarbonyl compounds to generate six oxazole rings, demonstrating the power of rhodium carbene methodology in organic chemical synthesis. CD spectroscopy establishes that seco-derivatives of telomestatin are potent stabilizers of G-quadruplex structures derived from the human telomeric repeat sequence. Mass spectrometry studies, confirmed by molecular dynamics simulations, provide the first evidence that high affinity binding to terminal G-tetrads in both 1:1 and 2:1 ligand complexes is mediated through the macrocycle coordinating a monovalent cation, with selectivity for the antiparallel structure.
- Linder, Joerg,Garner, Thomas P.,Williams, Huw E. L.,Searle, Mark S.,Moody, Christopher J.
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- Synthesis and application of N-3,5-dinitrobenzoyl and C3 symmetric diastereomeric chiral stationary phases
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Three diastereomeric chiral compounds, namely, (R,R)-(+)-2-amino-1,2-diphenylethanol, (1S,2R)-(+)-2-amino-1,2-diphenylethanol, and (1R,2R)-(+)-1,2-diphenylethylenediamine were used as starting materials for preparing three N-3,5-dinitrobenzoyl derivative
- Yu, Jeong Jae,Ryoo, Jae Jeong
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p. 587 - 596
(2022/01/20)
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- Radical-Mediated Acyl Thiol-Ene Reaction for Rapid Synthesis of Biomolecular Thioester Derivatives
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The thiol-ene ‘click’ reaction has emerged as a versatile process for carbon–sulfur bond formation with widespread applications in chemical biology, medicinal chemistry and materials science. Thioesters are key intermediates in a wide range of synthetic and biological processes and efficient methods for their synthesis are of considerable interest. Herein, we report the first examples of acyl-thiol-ene (ATE) for the synthesis of biomolecular thioesters, including peptide, lipid and carbohydrate derivatives. A key finding is the profound effect of the amino acid side chain on the outcome of the ATE reaction. Furthermore, radical generated thioesters underwent efficient S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’ ligation products in an overall amidation process with diverse applications for chemical ligation and bioconjugation.
- Lynch, Dylan M.,McLean, Joshua T.,McSweeney, Lauren,Milbeo, Pierre,Scanlan, Eoin M.
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supporting information
p. 4148 - 4160
(2021/08/24)
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- In search of small molecules that selectively inhibit mboat4
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Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.
- Ding, Hui,Harran, Patrick G.,Hollibaugh, Ryan A.,Liu, Haixia,Murzinski, Emily S.,Saha, Ishika,Strugatsky, David,Tontonoz, Peter
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- Late-Stage Intermolecular Allylic C-H Amination
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Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
- Clark, Joseph R.,Dixon, Charlie F.,Feng, Kaibo,Han, Wei,Ide, Takafumi,Koch, Vanessa,Teng, Dawei,Wendell, Chloe I.,White, M. Christina
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p. 14969 - 14975
(2021/10/01)
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- Chiral combinatorial preparation and biological evaluation of unique ceramides for inhibition of sphingomyelin synthase
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Enantiomers or diastereomers of chiral bioactive compounds often exhibit different biological and toxicological properties. Here, we report the efficient synthesis of four stereoisomers of sphingosine and derivatization of unique chiral ceramides through a combinatorial chemistry by solid-phase activated resin ester. In addition, to test the effectivity of stereochemistry of ceramide, we demonstrated a cell-based assay of sphingomyelin synthase inhibition in the presence ofchiral unique ceramides, which suggested that libraries of this sort will be a rich source of biologically active synthetic molecules.
- Koolath, Sajeer,Monde, Kenji,Murai, Yuta,Suga, Yoshiko
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supporting information
(2020/02/04)
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- Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate
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The invention discloses a method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. The method comprises the following steps: carrying out a reaction on D-serine and thionyl chloride in methanol to obtain a compound 2; carrying out a reaction on the compound 2 and Boc anhydride under triethylamine to obtain a compound 3; carrying out a reaction on the compound3 and 2,2-dimethoxypropane under the action of boron trifluoride diethyl ether to obtain a compound 4; and reducing the compound 4 and DIBAL-H are at a temperature of -60 DEG C to -80 DEG C to obtaina crude product, carrying out a reaction on the crude product and sodium sulfite to form salt, and purifying to obtain the high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. According to the invention, the salt forming is performed by using the properties of sodium sulfite and an aldehyde group, so that the purity of the salified product can reach 98%, the industrial standard is met, and the production operation is well facilitated.
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Paragraph 0061; 0071-0073
(2020/03/09)
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- Liposomal FRET Assay Identifies Potent Drug-Like Inhibitors of the Ceramide Transport Protein (CERT)
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Ceramide transfer protein (CERT) mediates non-vesicular transfer of ceramide from endoplasmic reticulum to Golgi apparatus and thus catalyzes the rate-limiting step of sphingomyelin biosynthesis. Usually, CERT ligands are evaluated in tedious binding assays or non-homogenous transfer assays using radiolabeled ceramides. Herein, a facile and sensitive assay for CERT, based on F?rster resonance energy transfer (FRET), is presented. To this end, we mixed donor and acceptor vesicles, each containing a different fluorescent ceramide species. By CERT-mediated transfer of fluorescent ceramide, a FRET system was established, which allows readout in 96-well plate format, despite the high hydrophobicity of the components. Screening of a 2 000 compound library resulted in two new potent CERT inhibitors. One is approved for use in humans and one is approved for use in animals. Evaluation of cellular activity by quantitative mass spectrometry and confocal microscopy showed inhibition of ceramide trafficking and sphingomyelin biosynthesis.
- Aglar, ?znur,Arenz, Christoph,Banhart, Sebastian,Cong, Xiaojing,Hamdo, Housam H.,Heuer, Dagmar,Kleuser, Burkhard,M?ller, Heiko M.,Saied, Essa M.,Samaha, Doaa,Schumacher, Fabian
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p. 16616 - 16621
(2020/11/30)
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- Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones
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The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Br?nsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. 1H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.
- Barber, David M.,Dixon, Darren J.,Thomson, Connor J.
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p. 5359 - 5364
(2020/02/28)
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- N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease
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Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer’s disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.
- Bae, Jae-sung,Choi, Min-Koo,Han, Seung Hoon,Jin, Hee Kyung,Kim, Hee-Jin,Kim, Seung Hyun,Lee, Ju Youn,Park, Cheol-Min,Park, Min Hee,Schuchman, Edward H.,Song, Im-Sook,Yu, Eunsoo
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- Methods and intermediates for synthesizing SK1-I
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The invention provides methods for synthesizing the compound (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I, and intermediate compounds used in its synthesis.
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Page/Page column 3; 4
(2019/08/20)
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- Stereoselective synthesis of unnatural (2S, 3S)-6-hydroxy-4-sphingenine-containing sphingolipids
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6-Hydroxy-(4E)-sphingenine-containing sphingolipids are found in mammalian and bacterial membranes and have multiple intra- and intercellular functions. Most sphingolipids contain a (2S,3R)-2-amino-1,3-diol core structure, but only limited examples of unnatural (2S,3S)-2-amino-1,3-diol derivates have so far been reported. Using an underexplored hydrozirconation-transmetalation reaction and an unusual three-step-one-pot deprotection sequence, we were able to synthesize several unnatural (2S,3S)-6-hydroxy-(4E)-sphingenine-containing sphingolipids in only three (protected) or four (deprotected) consecutive steps, respectively, including a fluoresence-labeled derivative suitable for future biological studies.
- Leichnitz, Daniel,Pflanze, Sebastian,Beemelmanns, Christine
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supporting information
p. 6964 - 6969
(2019/08/01)
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- Capturing Intermediates in the Reaction Catalyzed by NosN, a Class C Radical S-Adenosylmethionine Methylase Involved in the Biosynthesis of the Nosiheptide Side-Ring System
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Nosiheptide is a ribosomally synthesized and post-translationally modified thiopeptide natural product that possesses antibacterial, anticancer, and immunosuppressive properties. It contains a bicyclic structure composed of a large macrocycle and a unique
- Wang, Bo,Lamattina, Joseph W.,Marshall, Savannah L.,Booker, Squire J.
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supporting information
(2019/04/17)
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- Capturing Intermediates in the Reaction Catalyzed by NosN, a Class C Radical S-Adenosylmethionine Methylase Involved in the Biosynthesis of the Nosiheptide Side-Ring System
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Nosiheptide is a ribosomally synthesized and post-translationally modified thiopeptide natural product that possesses antibacterial, anticancer, and immunosuppressive properties. It contains a bicyclic structure composed of a large macrocycle and a unique
- Wang, Bo,Lamattina, Joseph W.,Marshall, Savannah L.,Booker, Squire J.
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supporting information
p. 5788 - 5797
(2019/04/17)
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- PRODRUGS OF GLUTAMINE ANALOGS
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Prodrugs of glutamine analogs, such as prodrugs of acivicin, are disclosed.
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Paragraph 0201
(2018/08/26)
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- MACROCYCLIC BROAD SPECTRUM 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 bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 001331
(2018/09/12)
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- Synthesis of a cisplatin derivative from lithocholic acid
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A new steroidal-platinum(II) hybrid compound was synthesized using a simple and efficient methodology. The synthesis was performed by a convergent approach with cross metathesis (CM) as a key step. An olefin derived from lithocholic acid and a vinyl substituted ethylenediamine derived from L-serine were used as chiral building blocks, which were combined in the CM step. The most important advantage of this method was the utilization of L-serine as a cheap, stereoisomerically pure substrate. A steroid with a diamino system in the side chain was subjected to reaction with potassium tetrachloroplatinate to obtain the target platinum(II) complex. Attempts to synthesize similar diamine systems using the asymmetric Strecker reaction were unsuccessful.
- Hryniewicka, Agnieszka,?otowski, Zenon,Seroka, Barbara,Witkowski, Stanis?aw,Morzycki, Jacek W.
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p. 5392 - 5398
(2018/02/12)
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- Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues
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The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl3-catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid-labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction.
- Yoshida, Masahito,Saito, Koya,Kato, Hikaru,Tsukamoto, Sachiko,Doi, Takayuki
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supporting information
p. 5147 - 5150
(2018/03/26)
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- Design, synthesis and structure-activity relationship studies of a novel focused library of 2,3,4-substituted oxazolidines with antiproliferative activity against cancer cell lines
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In the present work we describe the synthesis and antiproliferative evaluation of a focused library of 30 novel oxazolidines designed by modification of N-substituent, by ring variation, by alkyl variation or by extension of the structure. It was noted that carbamate and N,O-aminal groups were essential for activity. In general, replacement of the phenyl ring with pyridinyl was not tolerated. However, the introduction of a second phenyl ring with an appropriate spacer at the 3- or 4-position of the first phenyl ring generally enhanced the cytotoxic profile. Among all the prepared compounds, 24 was the most potent compound found in this class, being active on four of five cancer cell lines and it was 5-fold and 10-fold more potent than the lead compounds against HL60 and JURKAT cells, respectively. In addition, it showed relevant activity against MCF-7 and HCT-116 cells, which were resistant to lead. Moreover, 24 showed little antiproliferative activity against VERO, indicating low toxicity to normal cells. Thus, this compound has the potential to be developed as an anticancer agent.
- Andrade, Saulo F.,Oliveira, Bárbara G.,Pereira, Larissa C.,Ramos, Jonas P.,Joaquim, Angélica R.,Steppe, Martin,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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- As cell necrosis inhibitors of the indole compounds (by machine translation)
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The invention relates to chemical formula (1) indole compounds, or its pharmaceutically acceptable salt or isomer, and in containing the same as the characteristic, as an active ingredient for the prevention or treatment of cell necrosis and its associated disease composition and method of manufacturing. (by machine translation)
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Paragraph 0238; 0239
(2016/10/09)
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- INDOLE COMPOUND AS INHIBITOR OF NECROSIS
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The present invention relates to an indole compound represented by formula (1), a pharmaceutically acceptable salt or isomer thereof, a composition for prevention or treatment of necrosis and necrosis-associated diseases, and a method for preparing the composition, the composition comprising the indole compound or the pharmaceutically acceptable salt or isomer thereof as an active ingredient.
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Paragraph 0201
(2016/08/17)
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- ISOINDOLINE COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASE
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Isoindoline sigma-2 receptor antagonist compounds, pharmaceutical compositions comprising such compounds, and methods for inhibiting Abeta- associated synapse loss or synaptic dysfunction in neuronal cells, modulating an Abeta-associated membrane trafficking change in neuronal cells, and treating cognitive decline associated with Abeta pathology are provided.
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Paragraph 0481; 0483
(2015/09/23)
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- Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
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In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
- Nagaoka, Hikaru,Nishiwaki, Hisashi,Kubo, Takuya,Akamatsu, Miki,Yamauchi, Satoshi,Shuto, Yoshihiro
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p. 759 - 769
(2015/02/19)
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- An efficient one-pot oxidative esterification of aldehydes to carboxylic esters using B(C6F5)3-TBHP
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A simple and efficient protocol for oxidative esterification of diverse aldehydes with alcohols was accomplished with tert-butyl hydroperoxide and 1 mol % of tris(pentafluorophenyl)borane [B(C6F5)3] to generate the corresponding esters in good to excellent yields. The present protocol represents compatibility with wide range of functional groups as well as exceptional tolerance toward acid labile protecting groups such as TBDPS, TBDMS, acetonide, and Boc.
- Guggilapu, Sravanthi Devi,Prajapti, Santosh Kumar,Babu, Bathini Nagendra
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supporting information
p. 889 - 892
(2015/02/05)
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- BROMODOMAIN-INHIBITING COMPOUNDS AND PHARMACEUTICAL COMPOSITION COMPRISING SAME FOR PREVENTING OR TREATING A CANCER
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Provided is a novel compound having bromodomain and extra terminal domain (BET) protein inhibiting activities, and a pharmaceutical composition comprising the same which can be useful for prevention or treatment of precancerous transformation or cancer.
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- A process for the preparation of N-(1,1-Dimethylethyl)-(S)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate
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The present invention relates to a novel manufacturing method of N-Boc-(S)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate denoted by chemical formula 1, which does not go through a supercooling process whose temperature is 78 degree Celsius below zero by chemical formula 3 as a starting material, comprising a step of manufacturing N-[(1,1-dimethylethoxy)carbonyl]-2,2-dimethyloxazolidine methanol of a chemical formula 2 compound by reducing 3-(1,1-dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate of a chemical formula 3 compound under a reducing agent, an inorganic acid, or an acid catalyst of Lewis acid at room temperature.COPYRIGHT KIPO 2015
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Paragraph 0066-0074
(2016/12/22)
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- Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in Vitro cytotoxic evaluation
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We have previously reported the discovery of cytotoxic and pro-Apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3- oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-Apoptotic potential.
- Andrade, Saulo F.,Campos, Edmar F.S.,Teixeira, Claudia S.,Bandeira, Cristiano C.,Lavorato, Stefania N.,Romeiro, Nelilma C.,Bertollo, Caryne M.,Oliveira, M?nica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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p. 609 - 618
(2014/11/07)
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- METHODS FOR THE SYNTHESIS OF SPHINGOMYELINS AND DIHYDROSPHINGOMYELINS
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The present invention includes methods for the synthesis of sphingomyelins and dihydrosphingomyelins. The present invention also includes methods for the synthesis of sphingosines and dihydrosphingosines. The present invention further includes methods for the synthesis of ceramides and dihydroceramides.
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- METHODS FOR THE SYNTHESIS OF SPHINGOMYELINS AND DIHYDROSPHINGOMYELINS
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The present invention includes methods for the synthesis of sphingomyelins and dihydrosphingomyelins. The present invention also includes methods for the synthesis of sphingosines and dihydrosphingosines. The present invention further includes methods for the synthesis of ceramides and dihydroceramides.
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- Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation
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We have previously reported on a study of the structure-activity relationship in a series of 2,3,4-substituted oxazolidines recently discovered by our group varying the substituent at the ring or stereochemistry of the oxazolidine ring. We discovered the cytotoxic and pro-apoptotic potential of compounds 1 and 2 with good selectivity against cancer cell lines. In the present study we describe the synthesis and cytotoxic evaluation against cancer cell lines (HL60, JURKAT, MDA-MB-231 and LNCaP) of a series of oxazolidines designed by isosteric replacement or rigidification of the oxymethylene spacer of compounds 1 and 2. Alkenes 3 and 4 retained the activity against MDA-MB-231 cells and they were more active on HL60, JURKAT and LNCaP cells. Considering LNCaP cells, E-isomer 4 was at least 7 times and about 3 times more potent than lead 1 and Z-isomer 3, respectively. Compound 4 exerted significant activity against LNCaP with IC50 in the low micromolar range (11 μM) without affecting VERO cells and PBMC proliferation (IC50 > 100 μM) indicating its low toxicity to normal cells.
- Andrade, Saulo F.,Teixeira, Claudia S.,Ramos, Jonas P.,Lopes, Marcela S.,Pdua, Rodrigo M.,Oliveira, Mnica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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p. 1693 - 1699
(2014/12/11)
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- Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position
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Protein-protein interactions (PPIs) mediated by the polo-box domain (PBD) of polo-like kinase 1 (Plk1) serve important roles in cell proliferation. Critical elements in the high affinity recognition of peptides and proteins by PBD are derived from pThr/pS
- Qian, Wenjian,Park, Jung-Eun,Liu, Fa,Lee, Kyung S.,Burke Jr., Terrence R.
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p. 3996 - 4003
(2013/07/27)
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- HETEROBICYCLIC COMPOUNDS AS BETA-LACTAMASE INHIBITORS
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The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts, are useful in combination with beta-lactam antibiotics, or alone, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R 2, R 3 and R 4 are described herein.
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Page/Page column 169; 170
(2013/10/22)
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- Total synthesis and biological activity of natural product Urukthapelstatin A
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Herein we report the first total synthesis of the natural product Urkuthaplestatin A (Ustat A) utilizing a convergent synthetic strategy. The characterization and biological activity match those of the previously published natural product. Interestingly,
- Lin, Chun-Chieh,Tantisantisom, Worawan,McAlpine, Shelli R.
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p. 3574 - 3577
(2013/08/23)
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- Transformation of d-serine to highly functionalized cyclohexenecarboxylates in study of oseltamivir synthesis
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In an attempted synthesis of oseltamivir, D-serine was used to prepare (R)-Garner aldehyde, which reacted with vinylzinc reagent to give an alcohol product predominating in the (1′R,4S)-isomer. After the alcohol was protected as p-methoxybenzyl ether, the N,O-acetal was hydrolyzed and oxidized to an aldehyde, which underwent Reformatsky-type reaction with ethyl α-(bromomethyl)acrylate by promotion of indium to give an addition product readily for ring-closure metathesis to afford 3-alkoxy-4-amido-5-hydroxy-1- cyclohexenecarboxylates. After activation of the 5-hydroxy group as methanesulfonate, an attempted substitution reaction with sodium azide gave unexpectedly a cyclic carbamate via an intramolecular nucleophilic attack of the 4-tert-butoxycarbamate group.
- Lai, Joshua,Fang, Jim-Min
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scheme or table
p. 426 - 435
(2012/08/07)
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- Orthogonally protected glycerols and 2-aminodiols: Useful building blocks in heterocyclic chemistry
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The efficient synthesis of orthogonally protected glycerols, 2-aminopropane-1,3-diols and 2-aminobutane-1,4-diols that can constitute useful tools in heterocyclic chemistry, is reported. These interesting tri-functionalized small synthons were easily prepared from serine or aspartic acid. In addition, these substrates can be readily transformed into their iodide derivatives in very good yields. ARKAT USA, Inc.
- Ollivier, Anthony,Goubert, Marlene,Tursun, Ahmatjan,Canet, Isabelle,Sinibaldia, Marie-Eve
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experimental part
p. 108 - 126
(2010/10/03)
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- A concise synthesis of (2 S,3 S,4 S)-2-(hydroxymethyl)pyrrolidine-3,4-diol (LAB1)
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The synthesis of (2S,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol (LAB1) from Garners aldehyde is described using the Sharpless asymmetric dihydroxylation as the key step. Georg Thieme Verlag Stuttgart - New York.
- Upadhyay, Puspesh K.,Kumar, Pradeep
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scheme or table
p. 3063 - 3066
(2010/11/02)
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- 4,4-Difluorinated analogues of l-arginine and NG-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase
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4,4-Difluoro-l-arginine and 4,4-difluoro-NG-hydroxy-l-arginine were synthesized and shown to be substrates for the inducible isoform of nitric oxide synthase (iNOS). Binding of both fluorinated analogues to the NOS active site was also investigated using a spectral binding assay employing a heme domain construct of the inducible NOS isoform (iNOSheme). 4,4-Difluoro-NG-hydroxy-arginine was found to bind at the NOS active site in a unique manner consistent with a model involving ligation of the FeIII heme center by the oxygen atom of the NG-hydroxy moiety.
- Martin, Nathaniel I.,Woodward, Joshua J.,Winter, Michael B.,Marletta, Michael A.
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supporting information; experimental part
p. 1758 - 1762
(2009/11/30)
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- ASPARTYL PROTEASE INHIBITORS
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The invention provides compounds of the formula (I) wherein A is selected from the partial structures A1, A2 and A3; Ry and Ry' are both hydrogen, or Ry and Ry' together with the nitrogen atom to which they are attached form a cyclic amine such as morpholine, piperidine, piperazine or pyrrolidine; L is NHNH, CH2NH, O or S; Y is NH, NHNH, NHC(=O), S(=O)2NH, NHS(=O)2, CH2, CH2NH, O, S or S(=0)p; Q is aryl or heterocyclyl; Z is O, S, NRa or S(=0)p; m is O, 1 or 2; n is O, 1, 2 or 3; p is independently 1 or 2; q is 0 or 1; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C3-C7cycloalkylC0-C3alkyl, arylC0-C3alkyl or heterocyclylC0-C3alkyl, R4'' is H or C1-C6alkyl; or R4' and R4'' together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is H, C1-C6alkyl, C3-C7ycycloalkyl, aryl or heterocyclyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
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Page/Page column 93
(2009/05/28)
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- Cyclic peptide-polymer complexes and their self-assembly
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The efficient synthesis of novel chiral cyclic peptides cy-clo[NHCHX-CH=CHCH2CO(NHCH2-CH=CHCH2CO) 2] designed to develop hydrogen-bonding interactions with suitable polymers is described. Com-plexation of a carboxylic acid derivat-ized cyclic peptide 2 (X = CH2OCOCH2CH2CO2H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the ani-sotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hydrogen bonding is a useful approach for using polymers to mediate the self-assembly and self-organization of cyclic peptides.
- Belanger, Dominique,Tong, Xia,Soumare, Sadia,Dory, Yves L.,Zhao, Yue
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experimental part
p. 4428 - 4436
(2009/12/07)
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- The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
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Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
- Gauthier, Jacques Yves,Chauret, Nathalie,Cromlish, Wanda,Desmarais, Sylvie,Duong, Le T.,Falgueyret, Jean-Pierre,Kimmel, Donald B.,Lamontagne, Sonia,Leger, Serge,LeRiche, Tammy,Li, Chun Sing,Masse, Frederic,McKay, Daniel J.,Nicoll-Griffith, Deborah A.,Oballa, Renata M.,Palmer, James T.,Percival, M. David,Riendeau, Denis,Robichaud, Joel,Rodan, Gideon A.,Rodan, Sevgi B.,Seto, Carmai,Therien, Michel,Truong, Vouy-Linh,Venuti, Michael C.,Wesolowski, Gregg,Young, Robert N.,Zamboni, Robert,Black, W. Cameron
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p. 923 - 928
(2008/12/22)
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- Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)
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Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
- Jiang, Jian-Kang,Ghoreschi, Kamran,Deflorian, Francesca,Chen, Zhi,Perreira, Melissa,Pesu, Marko,Smith, Jeremy,Nguyen, Dac-Trung,Liu, Eric H.,Leister, William,Costanzi, Stefano,O'Shea, John J.,Thomas, Craig J.
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supporting information; experimental part
p. 8012 - 8018
(2009/12/07)
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- NEW COMPOUNDS
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The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X" is hydrogen, or when X' is fluoro, then X" may also be fluoro; R3is C1-C6alkyl; R4' is C1-C6alkyl; R4" is H or C1-C6alkyl; or R4' and R4" together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
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Page/Page column 55-56
(2008/12/07)
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- Complete structure elucidation of shishididemniols, complex lipids with tyramine-derived tether and two serinol units, from a marine tunicate of the family Didemnidae
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(Chemical Equation Presented) Two new serinolipid derivatives, shishididemniols A (1) and B (2), were isolated as antibacterial constituents of a tunicate of the family Didemnidae. The structure of 1 was elucidated by interpretation of spectral data and t
- Kobayashi, Hirotsugu,Ohashi, Jun'ichiro,Fujita, Tsuyoshi,Iwashita, Takashi,Nakao, Yoichi,Matsunaga, Shigeki,Fusetani, Nobuhiro
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p. 1218 - 1225
(2007/10/03)
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