- Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells
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Bioorthogonal decaging reactions are a promising strategy for prodrug activation because they involve bond cleavage to release a molecule of interest. The trans-cyclooctene (TCO)-tetrazine inverse electron-demand Diels-Alder reaction has been widely applied in vivo for decaging of amine prodrugs, however, the release of alcohol-containing bioactive compounds has been less well studied. Here, we report a TCO-carbamate benzyl ether self-immolative linker for the release of OH-molecules upon reaction with a tetrazine trigger. The benzyl ether linker proved to be highly stable and can rapidly liberate alcohols under physiological conditions upon reaction with tetrazines. The mechanism and decaging yield were systematically examined by fluorescence and HPLC analysis by using a fluorogenic TCO-benzyl ether-coumarin probe and different 3,6-substituted tetrazine derivatives. This study revealed that decaging occurs rapidly (t1/2 = 27 min) and the cycloaddition step happens within seconds (t1/2 = 7 s) with reaction rates of ≈100 M-1 s-1. Importantly, the reaction is compatible with living organisms as demonstrated by the decaging of a prodrug of the antibacterial compound triclosan in the presence of live E. Coli, that resulted in complete cell killing by action of the released "OH-active drug". Overall, this work describes a new linker for masking alcohol functionality that can be rapidly reinstated through tetrazine-triggered decaging.
- Davies, Sarah,Oliveira, Bruno L.,Bernardes, Gon?alo J. L.
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Read Online
- A DT-diaphorase responsive theranostic prodrug for diagnosis, drug release monitoring and therapy
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A DT-diaphorase-activatable theranostic prodrug, which contains camptothecin, a self-immolative linker and a trigger group, has been developed for the detection of DT-diaphorase, tracking of drug release and selectively killing cancer cells over-expressed
- Liu, Peilian,Xu, Jiangsheng,Yan, Donghang,Zhang, Peisheng,Zeng, Fang,Li, Bowen,Wu, Shuizhu
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Read Online
- Rational construction of probes rendering ratiometric response to the cancer-specific enzyme NQO1
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Pursuit of fluorescent probes for identification of cancer biomarkers benefits reliable predictions of early cancer detection. Here, a strategy employing polymeric micelle assembly for encapsulation of a new enzyme (NQO1)-responsive small molecule was est
- Fei, Qiang,Zhou, Li,Wang, Feiyi,Shi, Ben,Li, Chunbao,Wang, Rui,Zhao, Chunchang
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Read Online
- A double-triggered self-immolative spacer for increased selectivity of molecular release
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A self-immolative spacer based on dissymmetricalN,N′-bis-carbamate aniline is introduced to liberate a substrate from a precursor after dual activation. The proof of principle of its exclusive selectivity for substrate liberation has been conducted on a profluorophore.
- Huvelle, Steve,Le Saux, Thomas,Jullien, Ludovic,Schmidt, Frédéric
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supporting information
p. 240 - 246
(2021/12/29)
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- A class of intestinal lysis type co-drugs and their preparation and use
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The present invention relates to a class of intestinal cleavage type co-drugs (Codrug) and preparation and use thereof, in particular, the present invention provides a co-drug compound as shown in formula I. The present invention further provides a method
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Paragraph 0283-0288
(2022/01/20)
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- Turn on chemiluminescence-based probes for monitoring tyrosinase activity in conjunction with biological thiols
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We report a chemiluminescent probe (CLPT1) that permits the paired detection of tyrosinase (Tyr) and biological thiols. Tyr only leads to a poor chemiluminescence response, a finding ascribed to the formation of a stableo-benzoquinone intermediate. The addition of glutathione (GSH), or ascorbate to theo-benzoquinone intermediate results in thiol conjugation or reduction to this intermediate, respectively. This produces a strong chemiluminescence response. Thiol co-dependence was demonstrated in live cells using the cell permeable analogue,CLPT3. The present chemiluminescence-based strategy allows the concurrent detection of tyrosinase activity and biological thiols.
- Shelef, Omri,Sedgwick, Adam C.,Pozzi, Sabina,Green, Ori,Satchi-Fainaro, Ronit,Shabat, Doron,Sessler, Jonathan L.
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supporting information
p. 11386 - 11389
(2021/11/09)
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- Rational designed highly sensitive NQO1-activated near-infrared fluorescent probe combined with NQO1 substrates in vivo: An innovative strategy for NQO1-overexpressing cancer theranostics
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Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.
- Gong, Qijie,Yang, Fulai,Hu, Jiabao,Li, Tian,Wang, Pengfei,Li, Xiang,Zhang, Xiaojin
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- Discovery of a novel class of norovirus inhibitors with high barrier of resistance
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Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting in ~219,000 deaths annually and a societal cost of ~USD60 billion. There are no antivirals or vaccines available to treat and/or prevent HuNoV. In this study, we performed a large-scale phe-notypical antiviral screening using the mouse norovirus (MNV), which included ~1000 drug-like small molecules from the Drug Design and Synthesis Centre (Sapienza University, Rome). Compound 3-((3,5-dimethylphenyl)sulfonyl)-5-chloroindole-N-(phenylmethanol-4-yl)-2.carboxamide (compound 1) was identified as an inhibitor of MNV replication with an EC50 of 0.5 ± 0.1 μM. A series of 10 analogs were synthesized of which compound 6 showed an improved potency/selectiv-ity (EC50 0.2 ± 0.1 μM) against MNV; good activity was also observed against the HuNoV GI replicon (EC50 1.2 ± 0.6 μM). Time-of-drug-addition studies revealed that analog 6 acts at a time point that coincides with the onset of viral RNA replication. After six months of selective pressure, two compound 6res variants were independently selected, both harboring one mutation in VPg and three mutations in the RdRp. After reverse engineering S131T and Y154F as single mutations into the MNV backbone, we did not find a markedly compound 6res phenotype. In this study, we present a class of novel norovirus inhibitors with a high barrier to resistance and in vitro antiviral activity.
- La Regina, Giuseppe,Mastrangelo, Eloise,Matthijnssens, Jelle,Nalli, Marianna,Neyts, Johan,Puxeddu, Michela,Rocha-Pereira, Joana,Rymenants, Jasper,Sebastiani, Jessica,Silvestri, Romano,Tarantino, Delia,Van Dycke, Jana
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- Ortho-dithiol reactive treatment probe for drug release monitoring and preparation method of ortho-dithiol reactive treatment probe
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The invention discloses an ortho-dithiol reactive treatment probe for drug release monitoring and a preparation method of the ortho-dithiol reactive treatment probe. The structure of a probe compound is shown as a formula I in the specification. A probe m
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- COMPOUND HAVING BENZO SEVEN-MEMBERED RING STRUCTURE, PREPARATION METHOD THEREFOR, AND USE THEREOF
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The present invention relates to a compound having a benzo seven-membered ring structure, and a preparation method therefor, and use thereof. The compound has a structure as represented by formula (I). Provided is use of the compound having the structure and prepared with the preparation method of the present invention, enantiomers, diastereomers, racemates and mixtures thereof of the compound, as well as chemically acceptable salts, crystalline hydrates and solvent mixtures of the compound and the enantiomers, diastereomers, racemates and mixtures thereof of the compound in the preparation of drugs for treating BET Bromodomain BRD4 activity or expression level related diseases.
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- CEPHEM COMPOUNDS WITH LATENT REACTIVE GROUPS AND METHODS OF USING AND MAKING SAME
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The present application provides novel cephem, penem, and monobactam compounds that exhibit antibiotic activity against both Gram-negative and Gram-positive bacteria, as well as compositions comprising these compounds and methods of using these compounds and compositions to treat bacterial infections.
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Paragraph 0350-0351
(2020/10/19)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES
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Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.
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Page/Page column 93; 94
(2019/07/20)
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- METHOD OF PREPARING (3R,5R)-7-(2-(4-FLUOROPHENYL)-5-ISOPROPYL-3-PHENYL-4-((4-HYDROXYMETHYLPHENYLAMINO)CARBONYL)-PYRROL-1-YL)-3,5-DIHYDROXY-HEPTANOIC ACID HEMI CALCIUM SALT, INTERMEDIATES USED THEREIN, AND METHOD OF PREPARING THE INTERMEDIATES
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The present invention provides a method for manufacturing a (3r,5r)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxy-heptanoic acid hemi-calcium salt, an intermediate thereof, and a manufacturing method thereof. According to the present invention, the manufacturing method is performed in a convergent synthesis method of individually synthesizing each main structural part of the (3r,5r)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxy-heptanoic acid hemi-calcium salt and coupling the synthesized main structural parts. Accordingly, a flexible material can be easily controlled and manufacturing time can be reduced, thereby increasing productivity of a compound and yield of the final compound.COPYRIGHT KIPO 2019
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- CYCLOPENTAIMIDAZOLONES FOR THE TREATMENT OF CANCER
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Provided herein are compounds useful for the treatment of various proliferative diseases. These compounds, as well as pharmaceutically acceptable salts thereof may be formulated in pharmaceutical compositions, and may be used in methods of treatment and/o
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- LIVER PRODRUGS OF MITOCHONDRIAL PROTON IONOPHORES
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The present invention provides novel liver-targeted prodrugs of mitochondrial proton ionophores. These compounds have utility in medicine including their use in treatment of diseases such as NASH and NAFLD.
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Page/Page column 37; 38
(2018/06/06)
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- Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli
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In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening, we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB-TolC efflux pump in Escherichia coli. Herein, we present initial optimization efforts and structure-activity relationships around one of those previously described hits, NSC 60339 (1). From these efforts we identified two compounds, SLUPP-225 (17h) and SLUPP-417 (17o), which demonstrate favorable properties as potential EPIs in E. coli cells including the ability to penetrate the outer membrane, improved inhibition of efflux relative to 1, and potentiation of the activity of novobiocin and erythromycin.
- Haynes, Keith M.,Abdali, Narges,Jhawar, Varsha,Zgurskaya, Helen I.,Parks, Jerry M.,Green, Adam T.,Baudry, Jerome,Rybenkov, Valentin V.,Smith, Jeremy C.,Walker, John K.
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p. 6205 - 6219
(2017/08/02)
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- PRODUCTION METHOD FOR COMPOUND COMPRISING AMINO GROUP AND/OR HYDROXYL GROUP
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Disclosed is a method for producing a compound having an amino group and/or a hydroxyl group from a substrate compound having an atomic group containing CO or CS by eliminating said atomic group. The substrate compound having an atomic group containing CO or CS (for example, an amide, a carbamate, or the like) is allowed to react with a compound expressed by formula (I) below, at a temperature of 120°C or lower, preferably in the presence of an ammonium salt, to eliminate said atomic group containing CO or CS. In formula (I) A may not be present, and in a case where A is present, A represents an alkyl group having 1 to 6 carbon atoms. ????????H2N-A-NH2?????(I)
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Paragraph 0084
(2015/01/18)
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- 1-(CHLOROMETHYL)-2,3-DIHYDRO-1H-BENZO[E]INDOLE DIMER ANTIBODY-DRUG CONJUGATE COMPOUNDS, AND METHODS OF USE AND TREATMENT
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The invention provides antibody-drug conjugates comprising an antibody conjugated to a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) dimer drug moiety via a linker, and methods of using the antibody-drug conjugates.
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- Chemoselective hydrogenation of nitrobenzyl ethers to aminobenzyl ethers catalyzed by palladium-nickel bimetallic nanoparticles
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A highly efficient and chemoselective hydrogenation of nitrobenzyl ethers to aminobenzyl ethers was developed by using a novel palladium-nickel bimetallic nanocatalyst. Since the catalytic selectivity was resulted from the synergistic effects between two metals rather than the traditional catalyst poisons, the hydrogenation proceeded smoothly under additive-free conditions. Thus, the work-up procedure was as simple as to recover the catalyst by a magnetic separation and then to evaporate the solvent.
- Chen, Wenwen,Bao, Hailin,Wang, Dingsheng,Wang, Xinyan,Li, Yadong,Hu, Yuefei
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p. 9240 - 9244
(2015/11/27)
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- Cleavage of unactivated amide bonds by ammonium salt-accelerated hydrazinolysis
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Hydrazinolysis of unactivated amide bonds is significantly accelerated by the addition of ammonium salts. The reactions proceed at 50-70 °C to give amines with broad substrate scope that outperforms existing amide bond cleavage reactions. Application to peptide and amino sugar derivatives is also demonstrated. This journal is
- Shimizu, Yuhei,Noshita, Megumi,Mukai, Yuri,Morimoto, Hiroyuki,Ohshima, Takashi
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supporting information
p. 12623 - 12625
(2015/05/20)
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- Comparative study of the affinity and metabolism of type i and type II binding quinoline carboxamide analogues by cytochrome P450 3A4
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Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation, and aromatic hydroxylation. The results demonstrated that type II binding QCA analogues were metabolically less stable (2- to 12-fold) at subsaturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation > benzylic hydroxylation> O-demethylation > aromatic hydroxylation. Finally, for the QCA analogues with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine), indicating that electronegativity of the nitrogen can change regioselectivity in CYP metabolism.
- Dahal, Upendra P.,Joswig-Jones, Carolyn,Jones, Jeffrey P.
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experimental part
p. 280 - 290
(2012/03/10)
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- A mild and highly efficient method for the preparation of silyl ethers using Fe(HSO4)3/Et3N by chlorosilanes
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Avery efficient and mild procedure for preparation of silyl ethers from benzylic, allylic, propargilic alcohols, phenols, naphtoles and some of phenolic drugs with trimethylsilylchloride (TMSCl), triethylsilylchloride (TESCl) and t-buthyldimethylsilyl chloride (TDSCl) ethers in the presence of Fe(HSO 4)3/Et3N in roomtemperature in excellent yields is reported. This procedure also allows the excellent selectivity for silylation of alcohols and phenols.
- Abri, Abdolreza,Assadi, Mohammad Galeh,Pourreza, Samira
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p. 1449 - 1454
(2013/03/13)
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- QUATERNARY AMMONIUM SALT COMPOUNDS
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[Problem] The object of the present invention is to provide a novel compound having 132 adrenergic receptor agonist activity and muscarinic receptor antagonist activity. [Means for Solving the Problem] The present invention is a quaternary ammonium salt compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, with superior β32 adrenergic receptor agonist activity and muscarinic receptor antagonist activity.
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Page/Page column 22
(2012/03/10)
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- Mild and efficient PtO2-catalyzed one-pot reductive mono-N-alkylation of nitroarenes
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(Chemical Equation Presented) A mild and efficient one-pot reductive monoalkylation of nitroarenes has been described using aldehydes as alkylating agents, molecular hydrogen as a reducing agent, and PtO2 as a catalyst in methanol. This methodology is found to be applicable for both aliphatic and aromatic aldehydes and for a wide variety of nitroarenes. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Commuications to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
- Sreedhar, Bojja,Rawat, Vikas S.
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experimental part
p. 2490 - 2502
(2012/07/14)
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- Small molecule quantification by liquid chromatography-mass spectrometry for metabolites of drugs and drug candidates
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Identification and quantification of the metabolites of drugs and drug candidates are routinely performed using liquid chromatography-mass spectrometry (LC-MS). The best practice is to generate a standard curve with the metabolite versus the internal standard. However, to avoid the difficulties in metabolite synthesis, standard curves are sometimes prepared using the substrate, assuming that the signal for substrate and the metabolite will be equivalent. We have tested the errors associated with this assumption using a series of very similar compounds that undergo common metabolic reactions using both conventional flow electrospray ionization LC-MS and low-flow captive spray ionization (CSI) LC-MS. The differences in standard curves for four different types of transformations (O-demethylation, N-demethylation, aromatic hydroxylation, and benzylic hydroxylation) are presented. The results demonstrate that the signals of the substrates compared with those of the metabolites are statistically different in 18 of the 20 substrate-metabolite combinations for both methods. The ratio of the slopes of the standard curves varied up to 4-fold but was slightly less for the CSI method. Copyright
- Dahal, Upendra P.,Jones, Jeffrey P.,Davis, John A.,Rock, Dan A.
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experimental part
p. 2355 - 2360
(2012/03/26)
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- Gold catalysis: Tandem reactions of diyne-diols and external nucleophiles as an easy access to tricyclic cage-like structures
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Different diyne-diols composed of two terminal homopropargylic alcohol groups were prepared by bi-directional synthesis. Subjection of the syn diastereomers to NAC-gold catalysts (NAC=nitrogen acyclic carbene) in the presence of external nucleophiles such
- Hashmi, A. Stephen K.,Buehrle, Miriam,Woelfle, Michael,Rudolph, Matthias,Wieteck, Marcel,Rominger, Frank,Frey, Wolfgang
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supporting information; experimental part
p. 9846 - 9854
(2010/11/04)
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- Synthesis of an azide-tagged library of 2,3-dihydro-4-quinolones
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( Figure Presented ) We describe the assembly of a 960-member library of tricyclic 2,3-dihydro-4-quinolones using a combination of solution-phase high-throughput organic synthesis and parallel chromatographic purification. The library was produced with high efficiency and complete chemo- and diastereoselectivity by diversification of an azide-bearing quinolone via a sequence of [4 + 2] cycloadditions, N-acylations, and reductive aminations. The azide-functionalization of this library is designed to facilitate subsequent preparation of fluorescent or affinity probes, as well as small-molecule/surface conjugation.
- Lee, Hajoong,Suzuki, Masato,Cui, Jiayue,Kozmin, Sergey A.
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supporting information; experimental part
p. 1756 - 1759
(2010/05/18)
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- NOVEL THERAPEUTIC COMPOUNDS
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Disclosed herein are novel compounds of Formula (I), wherein the variables are defined as herein. The compounds of Formula (I) are useful as kinase inhibitors and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases as well as proliferative disorders such as cancer.
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Page/Page column 151-152
(2009/03/07)
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- SELF-IMMOLATIVE POLYMERS
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Self-immolative polymers, designed to release a chemical moiety, or a plurality of chemical moieties, upon a pre-determined cleavage event, or sequences of events, are disclosed. The polymers can be simple polymers, comb polymers or branched polymers. Fur
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Page/Page column 49-50
(2008/12/05)
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- Structure-activity relationship studies of phenanthridine-based Bcl-X L inhibitors
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Despite their structural similarities, the natural products chelerythrine (5) and sanguinarine (6) target different binding sites on the pro-survival Bcl-XL protein. This paper details the synthesis of phenanthridine-based analogues of the natu
- Bernardo, Paul H.,Wan, Kah-Fei,Sivaraman, Thirunavukkarasu,Xu, Jin,Moore, Felicity K.,Hung, Alvin W.,Mok, Henry Y. K.,Yu, Victor C.,Chai, Christina L. L.
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experimental part
p. 6699 - 6710
(2009/10/23)
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- Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus
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The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
- Xie, Hui,Ng, Danny,Savinov, Sergey N.,Dey, Barna,Kwong, Peter D.,Wyatt, Richard,Smith III, Amos B.,Hendrickson, Wayne A.
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p. 4898 - 4908
(2008/03/11)
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- THERAPEUTIC COMPOUNDS
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This invention relates to a novel class of substituted amino-ethoxy benzene derivatives of formula (I) which are inhibitors of serine proteases and to their use in treating aberrant serine protease activity in a mammal, contraception, anti-coagulant methods and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmummune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis and multiple sclerosis. (I), Wherein Rm, Rn, Rp, Rq, V, W, X, Y and R8 are as defined in the claims.
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Page/Page column 71
(2010/11/27)
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- INHIBITORS OF HISTONE DEACETYLASE
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This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula (I); wherein Y, L, Z, W, X, Q, R1, R2 and R3 are as defined in the specification.
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Page/Page column 71
(2010/11/24)
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- Protecting groups for glucuronic acid: Application to the synthesis of new paclitaxel (taxol) derivatives
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To prepare two new glucuronide conjugates, allyl ester and allyl carbonates were used as protecting groups of the glucuronic moiety. In this way, an aniline glycosyl carbamate spacer linked to the 2′-OH of paclitaxel was obtained. By using palladium chemistry, an efficient one-step removal of all the allyl groups at the end of the synthesis afforded the desired compounds in good yields.
- El Alaoui, Abdessamad,Schmidt, Frederic,Monneret, Claude,Florent, Jean-Claude
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p. 9628 - 9636
(2007/10/03)
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- BIPIPERIDINYL DERIVATIVES USEFUL AS INHIBITORS OF CHEMOKINE RECEPTORS
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In its many embodiments, the present invention provides a novel class of bipiperidinyl compounds as inhibitors of the CCR5 receptors, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with CCR5 using such compounds or pharmaceutical compositions. The invention also relates to the use of a combination of a compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
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Page/Page column 51
(2008/06/13)
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- SYNTHESIS OF PROTECTED PYRROLOBENZODIAZEPINES
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A method of synthesis of a N-10 protected PBD compound of formula (I) via an intermediate of formula (II) or formula (V).
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Page/Page column 44-45
(2010/02/11)
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- Identification of Novel Binding Interactions in the Development of Potent, Selective 2-Naphthamidine Inhibitors of Urokinase. Synthesis, Structural Analysis, and SAR of N-Phenyl Amide 6-Substitution
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The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1′ subsite; substitutions off of the phenyl group accessed S1′ and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to Ki = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as Ki = 6 nM, and many compounds had Ki 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.
- Wendt, Michael D.,Rockway, Todd W.,Geyer, Andrew,McClellan, William,Weitzberg, Moshe,Zhao, Xumiao,Mantei, Robert,Nienaber, Vicki L.,Stewart, Kent,Klinghofer, Vered,Giranda, Vincent L.
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p. 303 - 324
(2007/10/03)
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- Elongated multiple electronic cascade and cyclization spacer systems in activatible anticancer prodrugs for enhanced drug release
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The design and synthesis of several novel elongated self-elimination spacer systems for application in prodrugs is described. These elongated spacer systems can be incorporated between a cleavable specifier and the parent drug. Naphthalene- and biphenyl-containing spacers were synthesized but did not eliminate. Prodrugs of the anticancer agents doxorubicin and paclitaxel are reported that contain two or three electronic cascade spacers. A novel catalytic application of HOBt was found for the synthesis of N-aryl carbamates through reacting a 4-nitrophenyl carbonate with an aniline derivative, to connect the 1,6-elimination spacers via a carbamate linkage. In addition, a double spacer-containing paclitaxel prodrug was synthesized, comprising a 1,6-elimination spacer and a bis-amine linker connected to paclitaxel via a 2′-carbamate linkage. Prodrugs in which the novel spacer systems were incorporated between a specific tripeptide specifier and the parent drug doxorubicin or paclitaxel proved to be significantly faster activated by plasmin in comparison with prodrugs containing conventional spacer systems. It is expected that the generally applicable novel spacer systems reported herein will contribute to future development of improved enzymatically activated prodrugs.
- De Groot,Loos,Koekkoek,Van Berkom,Busscher,Seelen,Albrecht,De Bruijn,Scheeren
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p. 8815 - 8830
(2007/10/03)
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- Sequential energy and electron transfer in an artificial reaction center: Formation of a long-lived charge-separated state
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A novel molecular triad, representing an artificial reaction center, was synthesized via linking a fullerene moiety to an array of two porphyrins (i.e., a zinc tetraphenyl porphyrin (ZnP) and a free base tetraphenyl porphyrin (H2P)). In this Zn
- Luo,Guldi,Imahori,Tamaki,Sakata
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p. 6535 - 6551
(2007/10/03)
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- Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
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The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium m
- Shiraishi, Mitsuru,Aramaki, Yoshio,Seto, Masaki,Imoto, Hiroshi,Nishikawa, Youichi,Kanzaki, Naoyuki,Okamoto, Mika,Sawada, Hidekazu,Nishimura, Osamu,Baba, Masanori,Fujino, Masahiko
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p. 2049 - 2063
(2007/10/03)
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- Nonpeptide bradykinin antagonist analogs based on a model of a sterling-winthrop nonpeptide bradykinin antagonist overlapped with cyclic hexapeptide bradykinin antagonist peptides
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A proposed overlap between cyclic hexapeptide Bradykinin antagonists and nonpeptide Bradykinin antagonists is discussed. Structural variations on both the peptides and nonpeptides support the proposed overlap based on an increase or decrease in the biological activities of the antagonists.
- Dankwardt, Sharon M.,Ferla, Steven,Krstenansky, John L.,Bhakta, Sunil,Ostrelich, Helene,Jarnagin, Kurt
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p. 1921 - 1926
(2007/10/03)
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- Inhibition of human leukocyte elastase by functionalized N-aryl azetidin-2-ones: Substituent effects at C-3 and benzylic positions
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A series of functionalized N-aryl azetidin-2-ones with a latent alkylating group was prepared by a flexible four-step synthesis, They met criteria expected for a suicide-type inactivation of human leukocyte elastase (HLE) and porcine pancreatic elastase (
- Vergely,Boggetto,Okochi,Golpayegani,Reboud-Ravaux,Kobaiter,Joyeau,Wakselman
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p. 199 - 208
(2007/10/02)
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