- Diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid of the microsclerodermins and model studies for an end-game strategy for microsclerodermin B
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The first diastereoselective synthesis of the 5-hydroxy-pyrrolidinone amino acid common to eight members of the microsclerodermin family is presented. Our strategy involves formal hydration of an unsaturated precursor via the use of a two-step hydroxybromination-debromination protocol; this procedure provides exclusively the requisite 4,5-cis-pyrrolidinone. Furthermore model studies are presented that indicated the potential viability of this hydration strategy in the context of a synthesis of microsclerodermin B.
- Winter, Christian,Pullin, Robert D.C.,Donohoe, Timothy J.
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- Facile synthesis of 1,1-[2H2]-2-methylaminoethane-1-sulfonic acid as a substrate for taurine α ketoglutarate dioxygenase (TauD)
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Taurine α-ketoglutarate dioxygenase (TauD) is an archetypal α-ketoglutarate-dependent non-heme iron oxygenase. Here, we report a practical five-step synthetic route to 1,1-dideutero-2-methylaminoethanesulfonic acid hydrochloride, a useful alternative substrate for the characterization of deuterium kinetic isotope effects on TauD.
- McCusker, Kevin P.,Klinman, Judith P.
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- CD-sensitive Zn-porphyrin tweezer host-guest complexes, part 2: Cis- and trans-3-hydroxy-4-aryl/alkyl-β-lactams. A case study
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This article describes an application of the host-guest chiral recognition approach called tweezer methodology for the determination of the absolute configuration of 3-hydroxy-β-lactams. These substrates represent challenging cases due to their chemical reactivity, the presence of multiple stereogenic centers and several functional groups which offer various possibilities of binding to the Zn-porphyrin host. OPLS-2005, the force field used in this work to predict the interporphyrin twist, modeled correctly the host-guest complexation mechanism and revealed conformational details of the bound substrates. The computational study also suggested that in cases where an increase in the magnitude of the stereodifferentiation and an intense experimental CD are observed, the bound conformation of the conjugates are hydrogen bonded. The present investigation provides evidence that when the tweezer method is assisted by the OPLS-2005 based computational approach, it can be successfully applied to the con-figurational and conformational elucidation of multi-functional compounds with multiple stereogenic centers.
- Chen, Yihui,Petrovic, Ana G.,Roje, Marin,Pescitelli, Gennaro,Kayser, Margaret M.,Yang, Yan,Berova, Nina,Proni, Gloria
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- Preparation of 2-Substituted 3-Methoxycarbonyl-4-methoxyfurans that Allow Access to Highly Functionalized Naphthalenes via Regioselective Cycloaddition with Alkoxybenzyne
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A facile synthetic method of 2-substituted 3-methoxycarbonyl-4-methoxyfurans has been developed, allowing construction of highly functionalized naphthalene derivatives via (1) regioselective benzyne [4+2] cycloaddition with α-alkoxybenzyne and (2) reductive aromatization.
- Sato, Shogo,Kawada, Takuma,Takikawa, Hiroshi,Suzuki, Keisuke
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- Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones
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Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
- Salas-Ambrosio, Pedro,Tronnet, Antoine,Since, Marc,Bourgeade-Delmas, Sandra,Stigliani, Jean-Luc,Vax, Amelie,Lecommandoux, Sébastien,Dupuy, Bruno,Verhaeghe, Pierre,Bonduelle, Colin
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- pH-responsive host-guest polymerization and blending
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In this work, we demonstrate - in two different settings - the potential of the recognition motif made by tetraphosphonate cavitand/N-methyl ammonium salt for the development of supramolecular polymer chemistry. In the first part a novel pH sensitive supramolecular homopolymer was assembled by proper design of the corresponding monomer, and monitoring the self-assembling process by several analytical tools, including NMR spectroscopy and light scattering techniques. These measurements provided the evidence for the formation of the homopolymer and its pH responsiveness. In the second study, the two recognition groups - tetraphosphonate cavitand (Host) and sarcosine hydrochloride (Sarc) - introduced in polystyrene (PS-Host) and poly(butyl methacrylate) (PBMA-Sarc) respectively, led to the mixing of the two otherwise immiscible polymers thanks to the energetically favourable host-guest interactions between the polymer chains. The polymer blending was verified by the presence of a single glass transition temperature (Tg) and showed its homogeneous morphology by atomic force microscopy (AFM).
- Masseroni, Daniele,Rampazzo, Enrico,Rastrelli, Federico,Orsi, Davide,Ricci, Lucia,Ruggeri, Giacomo,Dalcanale, Enrico
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- Alkali-metal hexamethyldisilazide initiated polymerization on alpha-amino acid N-substituted N-carboxyanhydrides for facile polypeptoid synthesis
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Polypeptoids have been explored as mimics of polypeptides, owing to polypeptoids’ superior stability upon proteolysis. Polypeptoids can be synthesized from one-pot ring-opening polymerization of amino acid N-substituted N-carboxyanhydrides (NNCAs). However, the speed of polymerization of NNCAs can be very slow, especially for NNCAs bearing a bulky N-substitution group. This hindered the exploration on polypeptoids with more diverse structures and functions. Therefore, it is in great need to develop advanced strategies that can accelerate the polymerization on inactive NNCAs. Hereby, we report that lithium/sodium/potassium hexamethyldisilazide (Li/Na/KHMDS) initiates a substantially faster polymerization on NNCAs than do commonly used amine initiators, especially for NNCAs with bulky N-substitution group. This fast NNCA polymerization will increase the structure diversity and application of polypeptoids as synthetic mimics of polypeptides.
- Wu, Yueming,Zhou, Min,Chen, Kang,Chen, Sheng,Xiao, Ximian,Ji, Zhemin,Zou, Jingcheng,Liu, Runhui
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- Non-covalent immobilization of rare earth heterobimetallic frameworks and their reactivity in an asymmetric Michael addition
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Heterobimetallic Lewis acid catalysts are broadly useful and methods to recycle them have immediate applications. However, their immobilization through covalent binding can be challenging. Non-covalent immobilization of supported asymmetric catalysts is attractive due to ease of preparation and potential for reversible binding. We report a novel non-covalent binding strategy for Shibasaki's REMB framework {RE=rare earth metal; M=Li, Na, K; B=BINOL; RE:M:B=1:3:3, [M3(sol)n][(BINOLate)3RE]} and explore the reactivity of the supported catalyst.
- Robinson, Jerome R.,Yadav, Jagjit,Fan, Xinyuan,Stanton, Gretchen R.,Schelter, Eric J.,Pericas, Miquel A.,Walsh, Patrick J.
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- Cyclic poly(α-peptoid)s and their block copolymers from N-heterocyclic carbene-mediated ring-opening polymerizations of N-substituted N-carboxylanhydrides
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(Chemical Equation Presented) N-Heterocyclic carbene (NHC)-mediated ring-opening polymerization (ROP) of N-substituted N-carboxylanhydride ( NR-NCA) yields cyclic poly(4-peptoid)s with controlled molecular weights (Mn = 3-30 kg mol-1) and narrow molecular weight distributions (PDI = 1.04-1.12). The reactions exhibit characteristics of a living polymerization with minimal chain transfer. This enables the facile synthesis of cyclic diblock copoly(4-peptoid)s through sequential monomer addition. The cyclic polymer architectures were verified by MALDI-TOF mass spectrometry and intrinsic viscosity measurements. Mark-Houwink-Sakurada plot analyses revealed that cyclic poly(4-peptoid)s prepared from NHC-mediated polymerizations exhibit lower intrinsic viscosities than their linear analogues prepared from primary amine-initiated polymerizations. The ratio of their intrinsic viscosities is consistent with the former being mostly cyclic.
- Li, Guo,Donghui, Zhang
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- Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent "ene"-Reductases
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α-Tertiary amines are a common motif in pharmaceutically important molecules but are challenging to prepare using asymmetric catalysis. Here, we demonstrate engineered flavin-dependent ‘ene'-reductases (EREDs) can catalyze radical additions into oximes to prepare this motif. Two different EREDs were evolved into competent catalysts for this transformation with high levels of stereoselectivity. Mechanistic studies indicate that the oxime contributes to the enzyme templated charge-transfer complex formed between the substrate and cofactor. These products can be further derivatized to prepare a variety of motifs, highlighting the versatility of ERED photoenzymatic catalysis for organic synthesis.
- Gao, Xin,Turek-Herman, Joshua R.,Choi, Young Joo,Cohen, Ryan D.,Hyster, Todd K.
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supporting information
p. 19643 - 19647
(2021/12/01)
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- HETEROARYL COMPOUNDS
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Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00220
(2021/05/29)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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Compounds of formula (I') and methods of their use and preparation, as well as compositions comprising compounds of formula (I').
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Page/Page column 155
(2018/06/30)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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The present disclosure is directed to compounds of formula I and methods of their use and preparation, as well as compositions comprising compounds of formula I.
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Page/Page column 155
(2017/09/02)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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- AGONISTS THAT ENHANCE BINDING OF INTEGRIN-EXPRESSING CELLS TO INTEGRIN RECEPTORS
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A method of enhancing binding of cells to an integrin-binding ligand comprises treating integrin-expressing cells in vitro with an agonist of integrin, wherein the integrin is selected from the group consisting of α4β1, α5β1, α4β7, αvβ3 and αLβ2, and contacting the treated cells with an integrin-binding ligand; integrin agonist compounds having the general formula I; methods of treating integrin-expressing cells with such agonists to enhance binding; and therapeutic methods comprising administering agonist-treated cells or agonist compounds to a mammal.
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(2012/06/01)
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- Synthesis and cytotoxic activity of methyl glycyrrhetinate esterified with amino acids
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Methyl glycyrrhetinate was esterified at position C3 of ring A using different amino acids. A short, unbranched chain of four carbon atoms with two amino groups in positions 2 and 4 was shown to be the most active compound of this series (IC50 = 0:8 M on liposarcoma Lipo cells). These compounds trigger apoptosis as shown by an acridine orange/ethidium bromide assay, trypan blue tests and DNAladdering experiments.
- Csuk, Rene,Schwarz, Stefan,Siewert, Bianka,Kluge, Ralph,Stroehl, Dieter
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p. 731 - 746
(2012/11/13)
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- METABOTROPIC GLUTAMATE RECEPTORS 5 MODULATORS AND METHODS OF USE THEREOF
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Compounds that modulate GluR5 activity and methods of using the same are disclosed.
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Page/Page column 119-120
(2012/12/13)
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- DERMATOLOGICAL AGENT
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An object of the present invention is to provide dermatological agents such as whitening agents and hair growth accelerators that contain a compound having high water solubility and a specific structure capable of releasing 2,3-dimethoxy-5-methyl-1,4-dihydroxybenzene (reduced form). A dermatological agent according to the present invention contains a 2,3-dimethoxy-5-methyl-1,4-dihydroxybenzenecarboxylic acid ester derivative represented by the following general Formula (I) or a salt thereof: wherein in the Formula (I), R1, R2 and R3 are specific groups.
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(2011/06/26)
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- INHIBITOR OF ISCHEMIC DISORDERS
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It is intended to provide a drug which is efficacious in treating and preventing diseases wherein ischemia or an inflammatory substance associated with ischemia participates in the onset or worsening thereof. Because of containing as the active ingredient a substance selected from among farnesol, a farnesol derivative, a tocopherol derivative, a tocotrienol derivative, pharmacologically acceptable salts thereof and solvates thereof, the above-described inhibitor of ischemic disorders can exert therapeutic and preventive effects on diseases wherein ischemia or an inflammatory substance associated with ischemia participates in the onset or worsening thereof (for example, brain infarction, brain edema, cardiac infarction, etc.) not only by the administration in the acute ischemic stage but also by the therapeutic administration in subacute and/or chronic stages after ischemia-reperfusion. It is also intended to provide a farnesol carboxylic acid ester derivative and a method of producing the same.
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Page/Page column 11; 12
(2010/07/06)
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- P70S6 KINASE MODULATORS AND METHOD OF USE
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The invention provides compounds and methods for inhibition of kinases, more specifically p70S6 kinases. The invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism. Compounds of the invention inhibit, regulate and/or modulate kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above, and the invention includes compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions.
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(2008/06/13)
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- Total synthesis of hirsutellide A
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The total synthesis of hirsutellide A 1 was described. The linear hexadepsipeptide precursor 2 was synthesized in 45% yield from N-Boc-Me-Gly by three coupling reactions with DCC, HATU and BOP-Cl, respectively. Macrocyclization was successfully performed on the fully deprotected amino acid 14 with BOP-Cl in 15% yield and with FDDP in 22% yield.
- Xu, Yanjie,Chen, Ligong,Duan, Xuemin,Meng, Yi,Jiang, Liqin,Li, Meiling,Zhao, Guangle,Li, Yang
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p. 4377 - 4379
(2007/10/03)
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- Synthesis of the key precursor of Hirsutellide A
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Hexadepsipeptide 2, the precursor of Hirsutellide A (1), was synthesized in an overall yield of 45% from N-Boc-Me-Gly via three coupling reactions using dicyclohexylcarbodiimide (DCC), O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-Cl), respectively.
- Xu, Yanjie,Duan, Xuemin,Li, Meiling,Jiang, Liqin,Zhao, Guangle,Meng, Yi,Chen, Ligong
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p. 259 - 264
(2007/10/03)
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- Structure-activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs
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Structure-activity relationships on two novel potent cognition enhancing drugs, unifiram (DM232, 1) and sunifiram (DM235, 2), are reported. Although none of the compounds synthesised reached the potency of the parent drugs, some fairly active compounds have been identified that may represent new leads to develop other cognition enhancing drugs. An interesting result of this research is the identification of two compounds (13 and 14) that are endowed with amnesing activity (the opposite of the activity of the original molecules) and are nearly equipotent to scopolamine. Moreover, two compounds of the series (5 and 6) were found endowed with analgesic activity on a rat model of neuropathic pain at the dose of 1 mg/kg.
- Scapecchi, Serena,Martini, Elisabetta,Manetti, Dina,Ghelardini, Carla,Martelli, Cecilia,Dei, Silvia,Galeotti, Nicoletta,Guandalini, Luca,Romanelli, Maria Novella,Teodori, Elisabetta
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- Evaluation of chelating agents as anti-angiogenic therapy through copper chelation
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A set of novel polyamine hexadentate cis,cis-1,3,5,-triaminocyclohexane (tach) chelating agents were synthesized and evaluated in conjunction with a selection of both linear and macrocyclic polyamines as copper chelators for novel anti-angiogenic therapy in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity. Macrocyclic polyamine 15 exhibited the greatest selective activity in this assay while the tach based ligands exhibited cytotoxicity, but no selectivity. The evaluation of several sets of polyamine donor chelating agents including a selection of novel hexadentate 1,3,5-cis,cis-triaminocyclohexane (tach) based derivatives were performed in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity as novel anti-angiogenic agents. The selective nature of the anti-angiogenic agents for human umbilical vein endothelial cells (HUVEC) was compared to a normal fibroblast cell line and a human Glioma cell line to evaluate these compounds. Linear tri- and tetra-polyamines were superior to both macrocyclic and the tach based polyamine chelating agents in terms of selectivity of its inhibitory activity toward the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells. The linear polyamine, triethylenetetramine (22), previously reported to possess anti-angiogenic properties failed to demonstrate any selectivity for inhibiting the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells.
- Camphausen, Kevin,Sproull, Mary,Tantama, Steve,Venditto, Vincent,Sankineni, Sandeep,Scott, Tamalee,Brechbiel, Martin W.
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p. 5133 - 5140
(2007/10/03)
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- A synthetic strategy for the preparation of cyclic peptide mimetics based on SET-promoted photocyclization processes
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A novel method for the synthesis of cyclic peptide analogues has been developed. The general approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal phthalimides as light absorbing electron acceptor moieties and C-terminal α-amidosilane or α-amidocarboxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1) the lengths of the peptide chains separating the phthalimide and α-amidosilane or α-amidocarboxylate centers and (2) the nature of the penultimate cation radical α-heterolytic fragmentation process (i.e., desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.
- Yoon, Ung Chan,Jin, Ying Xue,Oh, Sun Wha,Park, Chan Hyo,Park, Jong Hoon,Campana, Charles F.,Cai, Xiaolu,Duesler, Eileen N.,Mariano, Patrick S.
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p. 10664 - 10671
(2007/10/03)
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- 1-METHYLCARBAPENEM DERIVATIVES
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The present invention relates to 1-methylcarbapenem compounds having excellent antibacterial activity, pharmacologically acceptable ester derivatives thereof, pharmacologically acceptable salts thereof, pharmaceutical compositions (particularly antibacterial agents) containing them as active ingredient, use of the compounds, ester derivatives or salts thereof for preparing such pharmaceutical compositions and a method of preventing or treating diseases (particularly bacterial infections) in which a pharmacologically effective amount of the compound, ester derivative or salt is administered to a warm-blooded animal (particularly a human being). The 1-methylcarbapenem compounds of the present invention are represented by the general formula (I): wherein:R1 is a group represented by the formula COOR3 (wherein R3 represents a hydrogen atom, a C1-C6 alkyl group or the like), a group represented by the formula CONR4R5 (wherein R4 and R5 each independently represent a hydrogen atom, a C1-C6 alkyl group which may be substituted or the like), a cyano group, a group represented by the formula CH2OR6 (wherein R6 represents a hydrogen atom, a C1-C6 alkyl group or the like) or a group represented by the formula CH2NR7R8 (wherein R7 represents a hydrogen atom, a C1-C6 alkyl group or the like, and R8 represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkanoyl group, a C1- C6 alkoxycarbonyl group or the like);R2 represents a hydrogen atom or a C1-C6 alkyl group;n represents 1, 2 or 3; andX represents a sulfur atom or an oxygen atom.
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- Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues
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The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin (1), and consequently it has been subjected to thorough preclinical evaluation and targeted for clinical evaluation. The details of the synthesis of hemiasterlin (1) and the analogues and a discussion of how their biological activities vary with their structures are presented in this paper.
- Nieman, James A.,Coleman, John E.,Wallace, Debra J.,Piers, Edward,Lim, Lynette Y.,Roberge, Michel,Andersen, Raymond J.
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p. 183 - 199
(2007/10/03)
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- Fused and bridged bi- and tri-cyclic lactams via sequential metallo-azomethine ylide cycloaddition-lactamisation
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Aldimines of α-amino esters derived from aldehydes bearing an α-, β- or γ-protected amino group undergo AgOAc/R3N catalysed cycloaddition to electronegative olefins (dipolarophile). Subsequent unmasking of the amino group and lactamisation, spontaneous in most cases, generates 5-7 membered fused and bridged bi- and tri-cyclic lactams. The regioselectivity of the lactamisation is controlled by appropriate choice of the dipolarophile.
- Blaney, Paul,Grigg, Ronald,Rankovic, Zoran,Thornton-Pett, Mark,Xu, Juan
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p. 1719 - 1737
(2007/10/03)
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- High molecular weight polymer-based prodrugs
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The present invention is directed compositions of the formula: STR1 wherein: D is a residue of biologically active moiety; X is an electron withdrawing group; Y and Y' are independently O or S; (n) is zero (0) or a positive integer, preferably from 1 to about 12; wherein: R1 and R2 are independently selected from the group consisting of H, C1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C1-6 alkyls; wherein: R3 is a substantially non-antigenic polymer, C1-12 straight or branched alkyl or substituted allyl, C5-8 cycloalkyl or substituted cycloalkyl, carboxyalkyl, carboalkoxy alkyl, dialkylaminoalkyl, phenylalkyl, phenylaryl or STR2 wherein: R4 and R5 are independently selected from the group consisting of H, C1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls, and substituted C1-6 alkyls or jointly form a cyclic C5 -C7 ring. In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.
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- Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity
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An improved synthesis of the hindered PEG-camptothecin diester transport form has been achieved using the Mukaiyama reagent. We have also assessed the effect of changing the electronic configuration of the (d-position of PEG-camptothecin transport forms on the rates of hydrolysis of the pro-moiety, and attempted to correlate these differences to efficacy in two animal models. In addition to the simple substitution of N for O, other synthetic modifications of these atoms were accomplished by employing heterobifunctional linker groups. The half lives by disappearance (rates of hydrolysis) of the transport forms in buffer and rat plasma were determined. It was established that anchimeric assistance to hydrolytic breakdown of the pro-moiety occurs in a predictable manner for some of these compounds. Results for the new derivatives in a P388 murine leukemic model and HT-29 human colorectal xenograft study are also presented. The use of a glycine linker group was found to provide similar efficacy in rodent models to that of simple camptothecin 20-PEG ester, and displayed enhanced pharmacokinetics. Copyright (C) 1998 Elsevier Science Ltd.
- Greenwald, Richard B.,Pendri, Annapurna,Conover, Charles D.,Lee, Chyi,Choe, Yun H.,Gilbert, Carl,Martinez, Anthony,Xia, Jing,Wu, Dechun,Hsue, Mei-mann
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p. 551 - 562
(2007/10/03)
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- Asymmetric synthesis of boc-N-methyl-p-benzoyl-phenylalanine. Preparation of a photoreactive antagonist of substance P
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The asymmetric synthesis of (S)-Boc-N-methyl-p-benzoyl-phenylalanine was performed by alkylation of sultam Boc-sarcosinate. The levorotatory sultam led to (S)-Boc-N-methyl amino acids with high optical purity. This photoreactive amino acid was incorporated into the sequence of a Substance P peptide antagonist. Comparison of the affinity and antagonistic properties of Biotinyl-apa-[D-Pro9, MePhe(pBz)10, Trp11]SP for human tachykinin NK-1 receptor demonstrated that this photoreactive antagonist should be a suitable tool for photolabelling studies.
- Karoyan, Philippe,Sagan, Sandrine,Clodic, Gil,Lavielle, Solange,Chassaing, Gerard
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p. 1369 - 1374
(2007/10/03)
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- High molecular weight polymer-based prodrugs
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The present invention is directed compositions of the formula: STR1 wherein: D is a biologically active moiety; X is an electron withdrawing group; Y and Y' are independently O or S; R1 is selected from the group consisting of H, C1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C1-6 alkyls; (n) is an integer from 1 to about 12; and R2 is a polyalkylene oxide. In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.
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- An approach towards more selective anticancer agents
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A promising approach towards better targeted anticancer drug therapy takes advantage of enhanced expression of proteases associated with human malignancies. Especially plasminogen activator activity has been found to be substantially increased, leading to an enhanced activity of the serine protease plasmin. Bifunctional alkylating agents, such as N-(2-chloroethyl)-N-nitrosoureas, display broad spectrum anticancer activity, but also exhibit considerable systemic toxicity. We describe here the synthesis of new N-nitrosourea-based prodrugs designed to become activated by tumor-associated proteases, to provide for enhanced antitumor activity and reduced systemic toxicity. Tripeptides representing substrates for plasmin were linked by an amide bond to N'-(2-aminoethyl)-N-(2-chloroethyl)-N-nitrosourea and the corresponding N'-methyl derivative. Synthesis and plasmin-triggered decomposition of these new tripeptide conjugates is described. Cancer cells expressing high plasminogen activator activity are highly sensitive to the new prodrugs in the presence of plasminogen, but not in its absence.
- Eisenbrand,Lauck-Birkel,Tang
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p. 1246 - 1258
(2007/10/03)
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- Complex Pyrrolidines via a Tandem Michael Reaction/1,3-Dipolar Cycloaddition Sequence. A Novel Method for the Generation of Unsymmetrical Azomethine Ylides
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A novel tandem Michael addition/1,3-dipolar cycloaddition protocol for the assembly of the 3,8-diazabicyclooctane ring system found in naphthyridinomycin (1) and quinocarcin (2) is described.
- Garner, Philip,Arya, Fariba,Ho, Wen-Bin
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p. 412 - 414
(2007/10/02)
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- Lyotropic Lipo-Amino-Acids: Synthesis and Structural Study
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Lyotropic lipo-amino-acids Cn(AA) where AA is one of the following amino-acids: glycine, alanine, sarcosine, serine, tyrosine, lysine, hydroxyethylglutamine, hydroxypropylglutamine, hydroxypentylglutamine and glutamic acid, and Cn is a paraffinic chain with 12 or 18 carbon atoms have been synthesized.The study by X-ray diffraction of the lipo-amino-acids in concentrated water solution and in the anhydrous state has shown the existence of two types of mesophases: lamellar and hexagonal.The respective influence of the water concentration, the nature of the amino-acid and the length of the paraffinic chain on the domain of stability of the mesophases and on the values of their structural parameters has been established.
- Gallot, B.,Hassan, H. Haj
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p. 195 - 214
(2007/10/02)
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- Quinolylglycinamide derivatives, the process for preparation thereof and their therapeutic application as psychotropic drugs
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The present invention relates to new quinolylglycinamide derivatives corresponding to the following general formula: STR1 The invention also relates to a process for preparing these compounds and their therapeutic application as a psychotropic agent.
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- PHOSPHONAMIDATE COMPOUNDS
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Phosphonamidates of the formula STR1 wherein X is a substituted or unsubstituted imino or amino acid or ester. These compounds possess angiotensin converting enzyme activity and are thus useful as hypotensive agents.
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