- Total Synthesis of the 7,10-Epimer of the Proposed Structure of Amphidinolide N, Part I: Synthesis of the C1-C13 Subunit
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Amphidinolide N, the structure of which has been recently revised, is a 26-membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10-epimer of the proposed structure of amphidinolide N, we have synthesized the C1-C13 subunit enantio- and diastereoselectively. Key reactions include an l-proline catalyzed enantioselective intramolecular aldol reaction, Evans aldol reaction, Sharpless asymmetric epoxidation and Tamao-Fleming oxidation. To aid late-stage manipulations, we also developed the 4-(N-benzyloxycarbonyl-N-methylamino)butyryl group as a novel ester protective group for the C9 alcohol.
- Ochiai, Koji,Kuppusamy, Sankar,Yasui, Yusuke,Okano, Tsubasa,Matsumoto, Yasunobu,Gupta, Nishant R.,Takahashi, Yohei,Kubota, Takaaki,Kobayashi, Jun'ichi,Hayashi, Yujiro
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Read Online
- MACROCYCLIC COMPOUNDS USEFUL AS CHITINASE INHIBITORS
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The present invention relates to macrocyclic compounds of formula (I) and their use as chitinase inhibitors as well as to pharmaceutical compositions and methods of preparation thereof. The compounds can in particular be used in the treatment, prevention and/or amelioration of asthma.
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Paragraph 0126; 0136-0137
(2021/07/29)
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- CONJUGATES OF A CELL-BINDING MOLECULE WITH CAMPTOTHECIN ANALOGS
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Provided are conjugates of camptothecin analogs with a cell-binding molecule of formula (I), wherein R1, R2, R3, R4, R5, X, L, n, m, T and ----- are defined herein. It also provides methods of making the conjugates of camptothecin analogs to a cell-binding agent, as well as methods of using the conjugates in targeted treatment of cancer, infection, and immunological disorders.
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Page/Page column 183
(2021/10/30)
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- Abolishing Dopamine D2long/D3Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2Receptor Agonists
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3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H2receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D2-like receptors (especially to the D3R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H1-4and D2long/3receptors. This study revealed a couple of selective candidates (among others31and47), and the most promising ones were screened at several off-target receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H2- and D2long/3-receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies.
- Tropmann, Katharina,Bresinsky, Merlin,Forster, Lisa,M?nnich, Denise,Buschauer, Armin,Wittmann, Hans-Joachim,Hübner, Harald,Gmeiner, Peter,Pockes, Steffen,Strasser, Andrea
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supporting information
p. 8684 - 8709
(2021/06/30)
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- CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES
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A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
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Page/Page column 133; 136; 161
(2020/01/31)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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Page/Page column 189-190; 256; 307
(2020/05/19)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Paragraph 000365; 000366
(2021/03/02)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Page/Page column 11; 181
(2019/07/17)
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- CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE
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What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.
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Paragraph 0574-0576; 0608-0610
(2020/01/08)
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- Selective Synthesis of (+)-Dysoline
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Dysoline, a novel chromone alkaloid isolated from Dysoxylum binectariferum, was reported to have selective cytotoxicity for HT1080 fibrosarcoma cells (IC50 of 0.21 μM). Given the scarcity of natural material, a concise synthesis of (+)-dysoline was developed, allowing for further biological evaluation. An enantioselective nucleophile-catalyzed aldol lactonization formed the piperidine ring with control of relative and absolute stereochemistry. Construction of the C6-chromone core with complete regioselectivity was achieved using a Danheiser benzannulation.
- Coffin, Aaron,Ready, Joseph M.
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supporting information
p. 648 - 651
(2019/01/26)
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- CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS
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The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.
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Page/Page column 155; 193
(2018/05/27)
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- Aldosterone derivative, preparation method thereof and aldosterone homogeneous enzyme immunoassay reagent
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The invention discloses an aldosterone derivative, a preparation method thereof, an aldosterone homogeneous enzyme immunoassay reagent and preparation and detection methods thereof. The aldosterone derivative has a structure shown as a formula (I), an aldosterone immunogen with high immunogenicity and an antibody of the aldosterone immunogen are prepared from the aldosterone derivative, and the aldosterone homogeneous enzyme immunoassay reagent prepared from the antibody can be used for realizing high-flux and high-speed detection of aldosterone on a fully-automatic biochemical analyzer.
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Paragraph 0070; 0082; 0088-0090
(2018/05/16)
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- LIPOPEPTIDE COMPOUNDS FOR THE TREATMENT OF PAIN DISORDERS
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The invention is based on the discovery of a new bacterial compound with analgesic properties which could be used as a new tool for the treatment of pain disorders such as visceral pain. Studying the mechanisms implicated in analgesic properties of the probiotic Escherichia coli strain Nissle 1917 (EcN), inventors characterized, the amino fatty acids produced by EcN, which display the Ecn analgesic properties. One of these compounds inhibits the hypersensitivity to colorectal distension induced by capsaicin, which is a very powerful nociceptive compound and acts via the GABA B receptor. Furthermore, inventors demonstrate that this compound is able to cross the cellular epithelial barrier (such as the intestinal epithelium). Thus, the invention relates to a lipopetide compound, derived from gamma-aminobutyric acid. The invention also relates to a lipopeptide compound according to the invention for the treatment of treating pain disorder, such as somatic pain and visceral pain.
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Page/Page column 18; 19; 20
(2018/11/22)
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- DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE
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Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
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Page/Page column 145
(2017/04/11)
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- Aldosterone derivative and aldosterone immunogen, synthesis methods thereof, specific antibody, aldosterone detection reagent, preparation method of detection reagent, and kit
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The invention discloses an aldosterone derivative and an aldosterone immunogen, synthesis methods thereof, a specific antibody, an aldosterone detection reagent, a preparation method of the detection reagent, and a kit, and belongs to the biotechnical field. The aldosterone immunogen has high immunogenicity, can be induced to obtain the high-tilter anti-aldosterone specific antibody, and has no cross reaction with 92 common interferents; and the aldosterone detection reagent prepared from the antibody can accurately and rapidly determine the content of aldosterone in a sample. Compared with existing commercial detection reagents, the detection reagent in the invention has the advantages of simplicity in operation, high sensitivity, high specificity, accuracy in result, effective reduction of the aldosterone detection cost, and facilitation of clinic large-scale promotion and use.
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Paragraph 0047; 0127; 0128; 0129; 0130; 0131; 0132
(2018/03/13)
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- SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF
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The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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Page/Page column 107-108
(2016/05/24)
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- SUBSTITUTED N-([1,1'-BIPHENYL]-3-YL)-[1,1'-BIPHENYL]-3-CARBOXAMIDE ANALOGS AS INHIBITORS FOR BETA-CATENIN/B-CELL LYMPHOMA 9 INTERACTIONS
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In one aspect, the invention relates to substituted N-([1,1'-biphenyl]-3-yl)-[1,1'- biphenyl]-3-carboxamide analogues, derivatives thereof, and related compound; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with β-Catenin/BCL9 protein-protein interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00432; 00433
(2017/01/31)
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- Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity
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Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure–activity relationships will be of interest for future studies on cell proliferation and immune modulation.
- Gromek, Samantha M.,deMayo, James A.,Maxwell, Andrew T.,West, Ashley M.,Pavlik, Christopher M.,Zhao, Ziyan,Li, Jin,Wiemer, Andrew J.,Zweifach, Adam,Balunas, Marcy J.
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supporting information
p. 5183 - 5196
(2016/10/24)
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- 4-Isopropylchroman-3-ol derivatives
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The present invention relates to a novel 4-isopropylchroman-3-ol compound, a pharmaceutical composition comprising the novel compound as an effective component, and to an intermediate compound useful for synthesizing the compound. When administered to a patient with a drug causing toxicity, the novel 4-isopropylchroman-3-ol compound exhibits efficacy of reducing toxicity of the drug by reducing antagonism regarding a T-type calcium channel and/or activity of cytochrome P450 isozyme.
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Paragraph 0237-0239
(2017/04/19)
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- Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate
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Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.
- Tarozzi, Andrea,Marchetti, Chiara,Nicolini, Benedetta,D'Amico, Massimo,Ticchi, Nicole,Pruccoli, Letizia,Tumiatti, Vincenzo,Simoni, Elena,Lodola, Alessio,Mor, Marco,Milelli, Andrea,Minarini, Anna
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p. 283 - 291
(2016/05/10)
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- 4 - (N-(4-amino-butyryl))-aminobutyric acid preparation method and application
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The invention provides a preparation method and application of 4-(N-(4-aminobutyryl))-aminobutyric acid. The preparation method comprises the following steps: by using gamma-aminobutyric acid (GABA) as the initial raw material, carrying out esterification protection, Carter condensation, sodium hydroxide/palladium-carbon hydrogenation reduction deprotection and the like to prepare the 4-(N-(4-aminobutyryl))-aminobutyric acid. The prepared 4-(N-(4-aminobutyryl))-aminobutyric acid is mainly used for detection of the 4-(N-(4-aminobutyryl))-aminobutyric acid content in the GABA raw material and GABA preparation. The GABA preparation comprises a GABA injection, a GABA sodium chloride injection, GABA for injection and the like. The preparation method has the advantages of accessible raw materials, simple reaction conditions and high yield and purity, is convenient to operate, and is suitable for laboratory and pilot-scale industrialized production of the 4-(N-(4-aminobutyryl))-aminobutyric acid. The product has stable properties, and is suitable for detection of GABA and related preparations.
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Paragraph 0059-0061
(2017/02/02)
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- Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interactions
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Selective inhibition of α-helix-mediated protein-protein interactions (PPIs) with small organic molecules provides great potential for the discovery of chemical probes and therapeutic agents. Protein Data Bank data mining using the HippDB database indicated that (1) the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix had few orientations when interacting with the second protein and (2) the hot spot pockets of PPI complexes had different sizes, shapes, and chemical groups when interacting with the same hydrophobic projecting hot spots of α-helix. On the basis of these observations, a small organic molecule, 4′-fluoro-N-phenyl-[1,1′-biphenyl]-3-carboxamide, was designed as a generic scaffold that itself directly mimics the binding mode of the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix. Convenient decoration of this generic scaffold led to the selective disruption of α-helix-mediated PPIs. A series of small-molecule inhibitors selective for β-catenin/B-cell lymphoma 9 (BCL9) over β-catenin/cadherin PPIs was designed and synthesized. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This new class of inhibitors can selectively disrupt β-catenin/BCL9 over β-catenin/cadherin PPIs, suppress the transactivation of canonical Wnt signaling, downregulate the expression of Wnt target genes, and inhibit the growth of Wnt/β-catenin-dependent cancer cells.
- Hoggard, Logan R.,Zhang, Yongqiang,Zhang, Min,Panic, Vanja,Wisniewski, John A.,Ji, Haitao
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supporting information
p. 12249 - 12260
(2015/10/12)
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- QUINONE-MASKED PROBES AS LABELING REAGENTS FOR CELL UPTAKE MEASUREMENTS
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Provided are labeling reagents and methods of using the reagents for cell uptake measurements. The labeling reagents can be quinone- masked probes including fluorophores and/or luminophores.
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Paragraph 00255
(2015/09/23)
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- SANTACRUZAMATE A COMPOSITIONS AND ANALOGS AND METHODS OF USE
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The compositions and methods described herein relate generally to Santacruzamate A compositions and analogs, which, among other features, are useful as histone deacetylase (HDAC) inhibitors.
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Page/Page column 44
(2014/02/16)
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- Efficient synthesis of mibefradil analogues: An insight into in vitro stability
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This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation. the Partner Organisations 2014.
- Lee, Ji Eun,Kwon, Tae Hui,Gu, Su Jin,Lee, Duck-Hyung,Kim, B. Moon,Lee, Jae Yeol,Lee, Jae Kyun,Seo, Seon Hee,Pae, Ae Nim,Keum, Gyochang,Cho, Yong Seo,Min, Sun-Joon
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supporting information
p. 5669 - 5681
(2014/07/22)
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- One-pot efficient synthesis of N α-urethane-protected β- And γ-amino acids
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1-[(4-Methylphenyl)oxy]pyrrolidine-2,5-dione and 1-[(4-methylphenyl)oxy] piperidine-2,6-dione react in a Lossen-type reaction with primary alcohols in the presence of triethylamine to furnish corresponding N α- urethane-protected β-alanine and γ-aminopropionic acid (GABA), respectively, with excellent yields and purities, in an essentially "one-pot" procedure.
- Cal, Marta,Jaremko, Mariusz,Jaremko, Lukasz,Stefanowicz, Piotr
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p. 1085 - 1091
(2013/07/05)
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- Photoinduced release of neurotransmitter amino acids from coumarin-fused julolidine ester cages
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The photoinduced release of several neurotransmitter amino acids (glycine, alanine, glutamic acid, β-alanine and γ-aminobutyric acid) was accomplished from ester cages based on a new photoremovable protecting group consisting of a coumarin built on the julolidine nucleus, namely a (11-oxo-2,3,5,6,7,11-hexahydro-1H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-9-yl) methyl group. Photolysis and steady-state sensitization studies revealed that release of the active molecule occurred in short irradiation times at long wavelengths, with a very promising performance at 419 nm. Given the interest in the development of novel protecting groups that are cleavable with UV A or even visible radiation, it was found that a structural modification in the coumarin ring by assembly of a fused julolidine leads to a promising photolabile protecting group for organic synthesis and also for bioapplications. Photolysis and steady-state sensitization studies of several neurotransmitter amino acids from ester cages based on a new photoremovable protecting group consisting of a coumarin-fused julolidine nucleus, revealed that the release of the active molecule occurred in short irradiation times at long wavelengths, especially at 419 nm. Copyright
- Piloto, Ana M.,Hungerford, Graham,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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p. 7715 - 7723
(2013/12/04)
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- MCR DENDRIMERS
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The invention relates to a method for producing peptoidic, peptidic and chimeric peptidic-peptoidic dendrimers by multiple iterative multi-component reactions (MCR), in particular Ugi or Passerini multi-component reactions, to compounds produced in this way and to the use thereof.
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Page/Page column
(2013/08/15)
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- Synthesis of functionalized glutamine- and asparagine-type peptoids-scope and limitations
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N-Alkylated glycine oligomers ('peptoids') can serve as potent peptidomimetic systems. Installing different functional groups can often be a challenge, and minimizes yields and purities. Here, we describe the synthesis of different amide-containing submonomers which were obtained as free bases, as well as their incorporation into peptoids. By using the free amines, the coupling results on solid support could be improved, and various functionalized peptoids were prepared. Additionally, an interesting dimerization side reaction leading to cross-linked peptoids was observed during synthesis.
- Cardenal, Carmen,Vollrath, Sidonie B. L.,Schepers, Ute,Br?se, Stefan
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p. 2237 - 2248
(2013/02/23)
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- NOVEL COMPOUNDS FOR MEDICAL USE AS PEPTIDASE EFFECTORS
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The invention relates to compounds of general formula (I) as set forth in the claims as well as to the use of the compounds of the general formula (1) in the medical field, specifically for use in the suppression of DNA synthesis and inflammatory cytokine production as well as in the stimulation of anti-inflammatory cytokine production in vitro and in vivo. This abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way.
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Page/Page column 82
(2012/02/06)
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- Synthesis of the isoquinoline alkaloid, crispine C
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The first total synthesis of the isoquinoline alkaloid, crispine C is described in seven steps using a Henry reaction and the Pictet-Gams variant of the Bischler-Napieralski reaction to effect the key transformations.
- Blair, Adele,Stevenson, Louise,Sutherland, Andrew
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supporting information; experimental part
p. 4084 - 4086
(2012/09/07)
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- Bichromophoric fluorescent photolabile protecting group for alcohols and carboxylic acids
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Novel bichromophoric fluorescent photolabile protecting group, (5-dansyloxy-3-hydroxynaphthalen-2-yl)methyl (DNS-NQMP), allows for the independent photochemical release and fluorescent imaging of caged substrates. Irradiation of DNS-NQMP-caged alcohols and carboxylic acids with 300 or 350 nm light results in fast (krelease ～ 105 s-1), efficient (Φ = 0.2), and quantitative release of the substrates. This uncaging chemistry is compatible with aqueous media and DNS-NQMP-protected hydroxy compounds are hydrolytically stable at neutral pH. Upon excitation with 400 nm light, caged compounds show intense green emission (λ max = 559 nm) with 21% fluorescence quantum yield. Fluorescent readout conducted using 400 nm or longer wavelengths does not cause substrate release. The DNS-NQMP chromophore retains its fluorescent properties after photo-uncaging reaction.
- Arumugam, Selvanathan,Popik, Vladimir V.
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scheme or table
p. 518 - 521
(2012/06/30)
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- A new diversity oriented and metal-free approach to highly functionalized 3H-pyrimidin-4-ones
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A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is presented. The strategy is based on the synthetic elaboration of readily available α-substituted β-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give 6H-1,3-oxazin-6-ones. These reactive intermediates have been in turn cleanly converted into highly functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence does not need the use of any metal mediator or catalyst.
- Riva, Renata,Banfi, Luca,Basso, Andrea,Zito, Paola
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experimental part
p. 2107 - 2122
(2011/05/08)
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- Synthesis of chiral cyclobutane containing C 3-symmetric peptide dendrimers
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(Figure Presented) Five new highly functionalized cyclobutane containing C3-symmetric peptide dendrimers have been synthesized through a convergent approach from 1,3,5-trisubstituted benzene and chiral λ,ε-amino diacid derivatives as well as a λ-tetrapeptide. The first example of the synthesis of N-centered amides by using 1,3,5-triaminobenzene and a carboxylic acid is reported.
- Gutierrez-Abad, Raquel,Illa, Ona,Ortuno, Rosa M.
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supporting information; experimental part
p. 3148 - 3151
(2010/08/20)
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- An autoimmolative spacer allows first-time incorporation of a unique solid-state fluorophore into a detection probe for acyl hydrolases
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A study was conducted to demonstrate the use of an autoimmolative spacer to incorporate a unique solid-state fluorophore into a detection probe for acyl hydrolases. The molecule effectively detected a model peptidase and showed elevated robustness that allowed for the adaptation to diffusion-resistant sequence-specific detection of peptidases for maximal spatial control. A cyclization linker was selected that immolated through an energetically favorable five- or six-membered transition state, taking into account the acylated O,O-acetal moiety. A GABA model compound was prepared to whether a GABA-based three-component system fragmented reliably.
- Zhang, Xiao-Bing,Waibel, Michael,Hasserodt, Jens
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supporting information; experimental part
p. 792 - 795
(2010/06/12)
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- 2-Oxo-2H-benzo[h]benzopyran as a new light sensitive protecting group for neurotransmitter amino acids
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Aiming at the development of new benzopyran-based photocleavable protecting groups, novel chloromethylated and hydroxymethylated 2-oxo-2H-benzo[h] benzopyran derivatives bearing a methoxy substituent were designed and used in the synthesis of a series of fluorescent bioconjugates, by linking through an ester or urethane bond to several model neurotransmitter amino acids (glycine, alanine, β-alanine and γ-aminobutyric acid, GABA). The resulting fluorescent bioconjugates with emission in the visible range and high fluorescent quantum yields, were subjected to photocleavage reaction in methanol/HEPES buffer (80:20) solution at different wavelengths of irradiation (250, 300, 350 and 419 nm) and photocleavage kinetic data were obtained.
- Soares, Ana M. S.,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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experimental part
p. 121 - 133
(2010/09/07)
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- Bacillus subtilis esterase (BS2) and its double mutant have different selectivity in the removal of carboxyl protecting groups
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An esterase from Bacillus subtilis (BS2) and its double mutant E188W/M193C quickly hydrolyze n-butyl, n-propyl, methoxyethyl and allyl esters. The wild-type BS2 preferentially removes such esters from the y-position of glutamate diesters, while the engineered enzyme has a reversed selectivity removing esters from the a-position of glutamate diesters. Automated docking and molecular dynamic simulations were performed to understand the molecular reason for the different regioselectivity.
- Barbayianni, Efrosini,Kokotos, Christoforos G.,Bartsch, Sebastian,Drakou, Christina,Bornscheuer, Uwe T.,Kokotos, George
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scheme or table
p. 2325 - 2332
(2009/12/28)
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- Formation of specific dipolar microenvironments complementary to dipolar betaine dye by nonionic peptide lipids in nonpolar medium
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This paper describes the host-guest interaction between nonionic peptide lipids and solvatochromic dipolar betaine dyes in nonpolar aprotic organic solvent. We have serendipitously found that the colour of Reichardt's Dye (referred to as Et(30) hereafter, although the term Et(30) has been used as a polarity parameter) in chlorobenzene unusually blue-shifted in the presence of L-glutamic acid-derived peptide lipid 1 with a benzyloxycarbonylated Gly headgroup. Since it is widely accepted that Et(30) shows negative solvatochromism, i.e., the visible absorption band of this dye blue-shifts as the solvent polarity increases, the blue-shift indicates that Et(30) was in contact with the more polar microenvironment produced by the peptide lipid 1 rather than chlorobenzene under aggregate-free conditions. The binding site was assumed to be N-Hδ+ and COδ- attached to both sides of the Gly residue, respectively, i.e., the O- and N + of Et(30) complementarily bound to N-Hδ+ and COδ- through hydrogen bonding and ion-dipole interaction, respectively. Since Et(30) is practically non-fluorescent, it was not feasible to use fluorescence spectrometry, which is a powerful method for the study of host-guest interactions, in order to specify the binding mode of Et(30). Therefore, a synthetic approach, although very laborious but reliable, has been used in conjunction with solvatochromic probing using visible absorption spectroscopy to specify the binding site on peptide lipid 1. The binding site has been found to be located on two dipoles, i.e., N-Hδ+ and COδ- attached to both sides of the Gly residue, respectively, because introducing steric hindrance into the Gly moiety using several L-α-amino acids with bulky α-substituents interfered with the binding of Et(30). Similar specific binding behaviour of Et(30) was observed by replacing the Gly residue of the lipid 1 with sarcosine (Sar). It was found that self-assembly of the peptide lipid was necessary for effective capture of Et(30). The molecular structural requirements of the peptide lipids that form such specific polar microenvironments complementary to dipolar betaine dyes have also been investigated. The Royal Society of Chemistry 2009.
- Hachisako, Hiroshi,Ryu, Naoya,Hashimoto, Hiromi,Murakami, Ryoichi
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supporting information; experimental part
p. 2338 - 2346
(2009/09/26)
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- Molecular structural requirements, dye specificity, and application of anionic peptide amphiphiles that induce intense fluorescence in cationic dyes
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We have previously reported that a double-chain anionic amphiphile capable of intermolecular triple hydrogen bonds could form extremely hydrophobic sites in water and specifically incorporated stilbazolium-based compact hemicyanine dyes as monomeric species, resulting in induction of intense fluorescence emission in the dyes. In this paper, the structural requirements of the intense fluorescence-inducing amphiphiles were investigated. It is noted that the introduction of β-Ala residues into two long-chain alkyl group moieties was most effective for the amphiphiles derived from L-glutamic acid with relatively shorter side-chain methylenes. The dye specificity in terms of induction of the intense fluorescence was also investigated using hemicyanines (stilbazolium etc.), cyanine, carbocyanine, thiacarbocyanines, and azo dye. The amphiphile with the shortest octanoyl-β-alanyl double-chain alkyl groups, longer side-chain, and shorter spacer was found to show increased sensitivity to alkali metal ions, especially Li+. This could be a potential OFF-ON type fluorescence sensor for Li+. The Royal Society of Chemistry 2009.
- Hachisako, Hiroshi,Ryu, Naoya,Murakami, Ryoichi
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supporting information; experimental part
p. 2327 - 2337
(2009/09/26)
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- 3-Aminoxypropionate-based linker system for cyclization activation in prodrug design
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A novel linker system based on 3-aminoxypropionate was designed and evaluated for drug release using proteolysis as an activation trigger followed by intramolecular cyclization. The hydroxylamine moiety present in the linker system enabled faster release of the parent drug from the linker-drug conjugate at lower pH as compared to an aliphatic amine moiety. Introduction of two methyl groups strategically at the α position to the carboxylate in the linker further improved the rate of cyclization by nearly 2-fold. The 3-aminoxypropionate linker was successfully applied to a model prodrug for protease activation using α-chymotrypsin as the activating enzyme; the activation of the model prodrug bearing the 3-aminoxypropionate linker was 136 times faster than the corresponding model prodrug bearing an amine linker.
- Ge, Yiyu,Wu, Xinghua,Zhang, Dazhi,Hu, Longqin
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scheme or table
p. 941 - 944
(2009/08/15)
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- Ruthenium tetroxide oxidation of cyclic N-acylamines by a single layer method: formation of ω-amino acids
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The ruthenium tetroxide oxidation of cyclic N-acyl amines by a 10% NaIO4 aqueous solution containing tert-butanol as a single layer system resulted in the endo-cyclic C-N bond cleavage to afford the ω-amino acids as almost sole products in good yields, while a similar oxidation under the double layer using a NaIO4 aqueous solution, and ethyl acetate gave the N-acyl lactams.
- Kaname, Mamoru,Yoshifuji, Shigeyuki,Sashida, Haruki
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p. 2786 - 2788
(2008/09/19)
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- Inhibitors interacting with the magnesium binding site of reverse transcriptase: Synthesis and biological activity studies of 3′-(Ω- amino-acyl) amino-3′-deoxy-thymidine
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Active site of reverse transcriptase contains carboxylate groups involved in the magnesium binding. We prepared some nucleoside analogs which could bind to these carboxylates preventing the binding of nucleotides. To the 3′-amino-3′-deoxy-thymidine, different N-protected ω-amino-acids were bound, the protection removed to give the 3′-(ω-amino-acyl-) amino-3′-deoxy-thymidines in good yield. Some showed moderate to low activity in HIV 1 replication test. Copyright Taylor & Francis Group, LLC.
- Goud, Thirumani Venkateshwar,Aubertin, Anne-Marie,Biellmann, Jean-Francois
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p. 495 - 505
(2008/09/21)
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- Synthesis, solution thermodynamics, and X-ray study of CuII [12]metallacrown-4 with GABA hydroxamic acid: An unprecedented crystal structure of a [12]MC-4 with a γ-aminohydroxamate
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The solution equilibria of γ-aminobutanehydroxamic acid (GABAha) with H+ and Cu2+ were investigated by potentiometry, titration calorimetry, spectrophotometry, NMR spectroscopy, and ESI-MS. The thermodynamic parameters of the CuII [12]metallacrown-4 obtained for GABAha were compared with those of the corresponding complexes of (S)-α-Alaha and β-Alaha. The stability (-ΔG0) sequence was β-Alahaa ? α-Alaha > GABAha, whereas the order of formation enthalpies (-ΔH0) was β-Alaha ? GABAha > α-Alaha. These data were interpreted on the basis of the dimensions of the chelate rings and the planarity of the metallamacrocycles. The CuII [12]metallacrown-4 ([12]MC-4) complex of GABAha was isolated and its crystal structure, which is the first reported for a [12]MC-4 of a γ-aminohydroxamic acid, fully supports the structural features interpreted from the thermodynamic data.
- Tegoni, Matteo,Ferretti, Luca,Sansone, Francesco,Remelli, Maurizio,Bertolasi, Valerio,Dallavalle, Francesco
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p. 1300 - 1308
(2007/10/03)
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- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
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(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
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p. 6162 - 6170
(2008/02/10)
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- Enzymatic removal of carboxyl protecting groups. III. Fast removal of allyl and chloroethyl esters by Bacillus subtilis esterase (BS2)
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(Chemical Equation Presented) An esterase from Bacillus subtilis (BS2) allows the fast and selective removal of allyl, 2-chloroethyl, and 2,2,2-chloroethyl esters under mild conditions in high yields. In addition, BS2 easily hydrolyzes phenacyl esters, while the hydrolysis of sterically hindered diphenylmethyl esters is slow, requiring longer reaction time and higher enzyme/substrate ratio.
- Fotakopoulou, Irene,Barbayianni, Efrosini,Constantinou-Kokotou, Violetta,Bornscheuer, Uwe T.,Kokotos, George
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p. 782 - 786
(2007/10/03)
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- Enzymatic removal of carboxyl protecting groups. 1. Cleavage of the tert-butyl moiety
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(Chemical Equation Presented) A recent discovery that a certain amino acid motif (GGG-(A)X-motif) in lipases and esterases determines their activity toward tertiary alcohols prompted us to investigate the use of these biocatalysts in the mild and selective removal of tert-butyl protecting groups in amino acid derivatives and related compounds. An esterase from Bacillus subtilis (BsubpNBE) and lipase A from Candida antarctica (CAL-A) were identified as the most active enzymes, which hydrolyzed a range of tert-butyl esters of protected amino acids (e.g., Boc-Tyr-OtBu, Z-GABA-OtBu, Fmoc-GABA-O tBu) in good to high yields and left Boc, Z, and Fmoc-protecting groups intact.
- Schmidt, Marlen,Barbayianni, Efrosini,Fotakopoulou, Irene,Hoehne, Matthias,Constantinou-Kokotou, Violetta,Bornscheuer, Uwe T.,Kokotos, George
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p. 3737 - 3740
(2007/10/03)
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- Enzymatic removal of carboxyl protecting groups. 2. Cleavage of the benzyl and methyl moieties
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Enzymes are versatile reagents for the efficient removal of methyl and benzyl protecting groups. An esterase from Bacillus subtilis (BS2) and a lipase from Candida antarctica (CAL-A) allow a mild and selective removal of these moieties in high yields without affecting other functional groups.
- Barbayianni, Efrosini,Fotakopoulou, Irene,Schmidt, Marlen,Constantinou-Kokotou, Violetta,Bornscheuer, Uwe T.,Kokotos, George
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p. 8730 - 8733
(2007/10/03)
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- Phospholipid prodrugs of anti-proliferative drugs
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The invention discloses prodrugs comprising anti-proliferative drugs covalently linked, via bridging group, to a phospholipid moiety such that the active species is preferentially released, preferably by enzymatic cleavage, at the required site of action. The invention further discloses pharmaceutical compositions said prodrugs and the uses thereof for the treatment of diseases and disorders related to inflammatory, to degenerative or atrophic conditions, and to uncontrolled cell growth. FIG.1depicts a graph of animal survival during the course of an experiment wherein mice were i.p. transplanted with 11210 mouse leukemia cells and then treated with vehicle only (squares), MTX (triangles) or molar equivalent dose of DP-MTX071 (circles) according to the regiment described example in Example 11.
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Page/Page column 11
(2010/02/08)
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- Radiolabelled bisphosphonates and method
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The present invention relates to 32P or 33P-labelled bisphosphonates as radiotherapeutic radiopharmaceuticals. The 32P- or 33P-labelled bisphosphonates, which are chemically identical to the unlabelled agent, are expected to target the lesion site in an identical manner, but also deliver a significant radiocytotoxic effect to the surrounding cells. This should result, given the favorable energetics of the β particle emission from the 33P nuclide, in a loss of proliferative capacity of cells associated with the tumor lesion. The relative stability and in vivo localisation of bisphosphonates makes them good candidates as 32P/33P delivery vehicles.
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- PHOSPHOLIPID DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
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Disclosed are compounds having non-steroidal anti-inflammatory drugs (NSAIDS) covalently linked to a phospholipid moiety via a bridging group. Also disclosed are a process for the synthesis of the compounds, pharmaceutical compositions comprising the compounds and the use thereof for the treatment of diseases and disorders related to inflammatory conditions.
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