- HETEROARYL DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS ACTIVE INGREDIENT
-
The present invention relates to a heteroaryl derivative and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient, and a compound according to an aspect of the present invention, a stereoisomer
- -
-
Paragraph 0156-0158
(2021/12/07)
-
- Efficient synthesis of NIR emitting bis[2-(2′-hydroxylphenyl)benzoxazole] derivative and its potential for imaging applications
-
Unassymetric bis[2-(2′-hydroxyphenylbenzoxole)] bis(HBO) derivatives with a DPA functionality for zinc binding have been developed with an efficient synthetic route, using the retrosynthetic analysis. Comparison of bis(HBO) derivatives with different substitution patterns allows us to verify and optimize their unique fluorescence properties. Upon binding zinc cation, bis(HBO) derivatives give a large fluorescence turn-on in both visible (λem ≈ 536 nm) and near-infrared (NIR) window (λem ≈ 746 nm). The probes are readily excitable by a 488 nm laser, making this series of compounds a suitable imaging tool for in vitro and in vivo study on a confocal microscope. The application of zinc binding-induced fluorescence turn-on is successfully demonstrated in cellular environments and thrombus imaging.
- Wang, Junfeng,Baumann, Hannah,Bi, Xiaoman,Shriver, Leah P.,Zhang, Zhaoda,Pang, Yi
-
-
- NEW CLASS OF DNA GYRASE AND/OR TOPOISOMERASE IV INHIBITORS WITH ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
-
The present invention relates to compounds having a structure of general formula (I), processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in humans and warm-blooded animals.
- -
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Page/Page column 60-61
(2020/03/29)
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- Total synthesis of inubosin B
-
Inubosin B is the most active member of the acridine alkaloids isolated from Streptomyces sp. IFM 11440 culture. The inubosins initiate neuroregeneration via a neurogenine 2 pathway. In this work, we have described the total synthesis of inubosin B via two synthetic routes. The effects of various coupling, cyclization and reduction reactions are discussed including common pitfalls and side reactions. Reverse phase chromatography with TFA was crucial for the isolation of the product from aluminum ions present in the reduction media.
- Hamissa, Mohamed Farouk,Niederhafner, Petr,?afa?ík, Martin,Telus, Marta,Kolá?ová, Lenka,Koutná, Leah,?estáková, Hana,Sou?ek, Radko,?ebestík, Jaroslav
-
supporting information
(2020/12/02)
-
- Diphenyl-aminopyrimidine compound for inhibiting kinase activity
-
The invention relates to a diphenyl-aminopyrimidine compound with an inhibiting function on protein tyrosine kinase, a pharmaceutical composition containing the diphenyl-aminopyrimidine compound, andpreparation and application of the diphenyl-aminopyrimidine compound, in particular to a compound shown as the formula (I) and pharmaceutically acceptable salt or crystal forms or prodrugs or metabolin or aquo-complex or solvate or isotope derivatives thereof, wherein R1, R2, R5, R6, R7, R8 and W are defined as the description. The compound can be used for treating ALK-mediated cancer related symptoms, such as non-small cell lung cancer or breast cancer or neural tumors or esophagus cancer or soft tissue cancer or lymphoma or leukemia. The formula is shown in the specification.
- -
-
Paragraph 0200; 0201; 0202; 0203; 0204; 0205
(2019/05/04)
-
- 3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature
-
Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C[sbnd]N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.
- Chaudhary, Renu,Natarajan, Palani,Rani, Neetu,Sakshi,Venugopalan, Paloth
-
supporting information
(2019/12/30)
-
- SPIROCYCLIC INDOLONE POLYETHYLENE GLYCOL CARBONATE COMPOUND, COMPOSITION, PREPARATION METHOD AND USE THEREOF
-
The present invention relates to a spirocyclic indolone polyethylene glycol carbonate compound, a composition thereof, a preparation method therefor, and a use thereof as an anticancer drug due to the antitumor activity thereof. The structural formula of the spirocyclic indolone polyethylene glycol carbonate compound is shown below. The compound has excellent tumor inhibitory activity, water solubility, low toxicity, and can be used for intravenous injection.
- -
-
Paragraph 0034; 0035
(2019/06/27)
-
- Spiroindolone polyethylene glycol carbonate compound, and compositions, preparation method and application thereof
-
The invention relates to a spiroindolone polyethylene glycol carbonate compound, compositions and a preparation method thereof, and an application of the spiroindolone polyethylene glycol carbonate compound as an anticancer drug due to antitumor activity of the spiroindolone polyethylene glycol carbonate compound. The spiroindolone polyethylene glycol carbonate compound has a structural formula asdescribed in the specification, has excellent tumor suppressive activity, good water solubility and low toxicity, and can be used for intravenous injections.
- -
-
Paragraph 0065-0068
(2018/04/03)
-
- Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
-
ATP-competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E. coli strain (MIC=6.25 μm) and against wild-type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N-phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.
- Durcik, Martina,Tammela, P?ivi,Baran?oková, Michaela,Toma?i?, Tihomir,Ila?, Janez,Kikelj, Danijel,Zidar, Nace
-
supporting information
p. 186 - 198
(2018/02/06)
-
- Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
-
The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
- Raj, Ganesh V.,Sareddy, Gangadhara Reddy,Ma, Shihong,Lee, Tae-Kyung,Viswanadhapalli, Suryavathi,Li, Rui,Liu, Xihui,Murakami, Shino,Chen, Chien-Cheng,Lee, Wan-Ru,Mann, Monica,Krishnan, Samaya Rajeshwari,Manandhar, Bikash,Gonugunta, Vijay K.,Strand, Douglas,Tekmal, Rajeshwar Rao,Ahn, Jung-Mo,Vadlamudi, Ratna K.
-
supporting information
(2017/09/18)
-
- Synthesis of the γ-Secretase Modulator MK-8428
-
The synthesis of the γ-secretase modulator MK-8428 (1) is described. The synthesis is highlighted by an enzyme-catalyzed reaction to access 3,4,5-trifluoro-(S)-phenylglycine, a 1-pot activation/displacement/deprotection sequence to introduce the aminooxy functionality and a dehydrative intramolecular cyclization under mild conditions to form the oxadiazine heterocycle of 1. In situ reaction monitoring was employed to understand the deleterious role of water during the formation of a methanesulfonate ester in the 1-pot activation/displacement/deprotection sequence.
- Miller, Steven P.,Morris, William J.,Orr, Robert K.,Eckert, Jeffrey,Milan, Jay,Maust, Mathew,Cowden, Cameron,Cui, Jian
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p. 2957 - 2964
(2017/03/23)
-
- CYSTOBACTAMIDES
-
The present invention provides cystobactamides of formula (I) and the use thereof for the treatment or prophylaxis of bacterial infections:
- -
-
Paragraph 0548; 0559; 0560; 0561
(2016/06/13)
-
- Synthesis and biological evaluation of cystobactamid 507: A bacterial topoisomerase inhibitor from Cystobacter sp.
-
Abstract The first total synthesis of cystobactamid 507, a member of a class of new natural products with strong inhibitory activity towards bacterial topoisomerases, is reported. Synthetic key challenges are the central tetrasubstitued arene and the low chemical reactivity of anilines and ortho-phenolic and isopropoxy-substituted benzoic acids. Biological evaluations demonstrate that cystobactamid 507 inhibits several Gram-positive pathogens but at significantly lower concentrations than described for the larger members of this natural product family.
- Moreno, María,Elgaher, Walid A.M.,Herrmann, Jennifer,Schl?ger, Nadin,Hamed, Mostafa M.,Baumann, Sascha,Müller, Rolf,Hartmann, Rolf W.,Kirschning, Andreas
-
supporting information
p. 1175 - 1178
(2015/06/02)
-
- Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
-
β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
- Mok, N. Yi,Chadwick, James,Kellett, Katherine A. B.,Casas-Arce, Eva,Hooper, Nigel M.,Johnson, A. Peter,Fishwick, Colin W. G.
-
supporting information
p. 1843 - 1852
(2013/05/08)
-
- PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
-
Compounds of the formula I or II: wherein X, m, Ar, R1 and R2 are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.
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Page/Page column 60
(2012/02/01)
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- Exploring the interplay of physicochemical properties, membrane permeability and giardicidal activity of some benzimidazole derivatives
-
This study evaluated the relationship between the physicochemical properties, membrane permeability and in vitro giardicidal activity of twenty nine benzimidazole derivatives (1-7n). The retention time data from reverse phase high performance chromatography (RP-HPLC) were used to estimate aqueous solubility and lipophilicity of these compounds. The apparent permeability was determined using Caco-2 cell monolayer. The calculation of some descriptors, such as Clog P, PSA, was performed using ACD labs software. For benzimidazole derivatives with NHCOOCH3, CH3, NH2, SH and SCH3 groups at the 2-position, a quadratic type of regression model was obtained with giardicidal activity and aqueous solubility or lipophilicity. On the other hand, giardicidal activity of 2-(trifluoromethyl)-1H-benzimidazole derivatives was influenced by lipophilicity, hydrogen bond donors and molecular volume but it was not determined by their apparent permeability in Caco-2 cell line.
- Hernández-Covarrubias, Carlos,Vilchis-Reyes, Miguel A.,Yépez-Mulia, Lilian,Sánchez-Díaz, Remedios,Navarrete-Vázquez, Gabriel,Hernández-Campos, Alicia,Castillo, Rafael,Hernández-Luis, Francisco
-
scheme or table
p. 193 - 204
(2012/07/27)
-
- GAMMA SECRETASE MODULATORS
-
In its many embodiments, the present invention provides a novel class of heterocyclic compounds of Group A or Group, as defined herein, as modulators of gamma secretase, 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 the central nervous system using such compounds or pharmaceutical compositions
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-
Page/Page column 138-139
(2010/06/15)
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- GAMMA SECRETASE MODULATORS
-
In its many embodiments, the present invention provides a novel class of heterocyclic compounds of the formula: as modulators of gamma secretase, 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 the central nervous system using such compounds or pharmaceutical compositions.
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Page/Page column 360
(2010/06/15)
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- UREA TYPE CINNAMIDE DERIVATIVE
-
Disclosed is a compound represented by the formula (I) below or a pharmacologically acceptable salt thereof. Also disclosed is a use of the compound or salt as a pharmaceutical product. (In the formula, Ar1 represents an imidazolyl group which may be substituted with a C1-6 alkyl group; Ar2 represents a phenyl group which may be substituted with a C1-6 alkoxy group; X1 represents a single bond; R1 and R2 respectively represent a C1-6 alkyl group or the like which may be substituted with a substituent such as a 5- to 14-membered aromatic heterocyclic group; and R3 represents a hydrogen atom or the like.)
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Page/Page column 48
(2009/02/10)
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- PLATELET ADP RECEPTOR INHIBITORS
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Compounds are provided which are useful as platelet ADP receptor inhibitors, for treating thrombosis and for reducing the likelihood and/or severity of a secondary ischemic event in a patient.
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Page/Page column 53-54
(2008/06/13)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
-
A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
-
- A scalable synthesis of MN-447, an antagonist for integrins αvβ3 and αIIbβ 3
-
(2S)-Benzeneslfonylamino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2- ylamino)piperidin-1-yl}benzoylamino]propionic acid, MN-447, is a potent antagonist of the integrins αvβ33 and αIIbβ3 Herein, we report a novel synthetic protocol that produces MN-447 in an overall yield of 45%. This protocol, when compared with the original synthetic route for MN-447, is more cost-effective, requires fewer steps, does not require chromatographic purification of intermediates and MN-447, and increases the overall yield by 35%. This report focuses on the synthetic strategies that were developed for this protocol. Now, the large quantities of MN-447 that are needed for preclinical and toxicological studies can be readily obtained.
- Ishikawa, Minoru,Tsushima, Masaki,Kubota, Dai,Yanagisawa, Yumiko,Hiraiwa, Yukiko,Kojima, Yasuo,Ajito, Keiichi,Anzai, Naomichi
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p. 596 - 602
(2013/01/03)
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- PROCESS FOR PRODUCTION OF CINNAMAMIDE DERIVATIVE
-
A compound (8) represented by the formula: (8) wherein R1 represents a 6- to 14-membered aromatic hydrocarbon ring group which may have a substituent; and n represents 0 to 2, can be produced with good efficiency by reacting a compound (3) represented by the formula: (3) wherein R1 and n are as defined above; and Q represents a single bond or -CH(Y)- where Y represents a hydrogen atom or a C1-6 alkyl group] with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the presence of a base.
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-
Page/Page column 50
(2008/12/07)
-
- SALTS OF CYNNAMIDE COMPOUND OR SOLVATES THEREOF
-
The invention provides crystals of dihydrochloride monohydrate of the compound of the following formula having an Aβ production inhibiting effect which crystals are characterized by exhibiting a diffraction peak at an angle of diffraction (2θ ± 0.2°) of 10.9° in powder X-ray diffractometry. Further, the invention also provides the compound in the form of various salts, crystal forms and amorphous forms which are suitable for the development of drugs.
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Page/Page column 14
(2008/12/07)
-
- Morpholine type cinnamide compound
-
The present invention relates to a compound represented by the formula (I): or a pharmacologically acceptable salt thereof, wherein R1, R2, R3, and R4 are the same or different and each represent a hydrogen atom or a C1-6 alkyl group; X1 represents a C1-6 alkylene group that may be substituted; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, provided that Xb is only an oxygen atom when Xa is a methoxy group; and Ar1 represents an aryl group, pyridinyl group, aryloxy group, or pyridinyloxy group that may have a substituent such as a halogen atom; and to use of the compound or salt as a pharmaceutical agent.
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-
Page/Page column 31-32
(2008/06/13)
-
- Multi-cyclic cinnamide derivatives
-
The present invention provides a compound represented by the formula (I): or a pharmacologically acceptable salt thereof, wherein Ar1 represents an imidazolyl group that may be substituted with a C1-6 alkyl group, or the like, Ar2 represents a phenyl group that may be substituted with a C1-6 alkoxy group, or the like, X1 represents a double bond or the like, and Het represents an imidazolyl group that may be substituted with a C1-6 alkyl group, or the like, which is effective as a therapeutic or prophylactic agent for a disease caused by Aβ.
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Page/Page column 62
(2010/11/28)
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- Next-generation spirobenzazepines: Identification of RWJ-676070 as a balanced vasopressin V1a/V2 receptor antagonist for human clinical studies
-
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V1a/V2 receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.
- Xiang, Min Amy,Rybczynski, Philip J.,Patel, Mona,Chen, Robert H.,McComsey, David F.,Zhang, Han-Cheng,Gunnet, Joseph W.,Look, Richard,Wang, Yuanping,Minor, Lisa K.,Zhong, H. Marlon,Villani, Frank J.,Demarest, Keith T.,Damiano, Bruce P.,Maryanoff, Bruce E.
-
p. 6623 - 6628
(2008/03/18)
-
- Cinnamide compound
-
The present invention relates to a compound represented by Formula (I): (wherein Ar1 represents an imidazolyl group which may be substituted with 1 to 3 substituents; Ar2 represents a pyridinyl group, a pyrimidinyl group, or a phenyl group which may be substituted with 1 to 3 substituents; X1 represents (1) —C≡C— or (2) a double bond etc. which may be substituted; R1 and R2 represent, for example, a C1-6 alkyl group or C3-8 cycloalkyl group which may be substituted) or a pharmacologically acceptable salt thereof and to the use thereof as pharmaceutical agents. The object of the present invention is to find a therapeutic or preventive agent for diseases caused by Aβ. According to the present invention, a therapeutic or preventive agents for diseases caused by Aβ can be provided.
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-
Page/Page column 49
(2008/06/13)
-
- 2,4-DIOXO-3-QUINAZOLINYLARYL SULFONYLUREAS
-
2,4-Dioxo-3-quinazolinylaryl sulfonylurea compounds are provided that are useful for the inhibition of ADP-platelet aggregation, particularly in the treatment of thrombosis and thrombosis related conditions or disorders.
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-
Page/Page column 52
(2008/06/13)
-
- Process for the preparation of nonpeptide substituted spirobenzoazepine derivatives
-
Novel spirobenzoazepine compounds, novel processes for the preparation of nonpeptide substituted spirobenzoazepine derivatives, and novel processes for the preparation of intermediates in the preparation of such derivatives. Novel intermediates in the preparation of nonpeptide substituted spirobenzoazepine derivatives.
- -
-
-
- Substituted spirobenzazepines
-
The invention is directed to nonpeptide substituted benzazepines of Formula I, which are useful as vasopressin receptor antagonists for treating conditions associated with vasopressin receptor activity such as those involving increased vascular resistance and cardiac insufficiency, including congestive heart failure, hyponatremia, and hypertension, among others disclosed. Pharmaceutical compositions comprising a compound of Formula I and methods of treating conditions such as hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, hyponatremia, renal vasospasm, renal failure, diabetic nephropathy, cerebral edema, cerebral ischemia, stroke, thrombosis, or water retention are also disclosed.
- -
-
-
- Benzimidazole derivatives
-
Disclosed are compounds represented by the following chemical formula (I) and pharmacologically acceptable salts thereof which are novel compounds useful as anticancer agents, antiviral agents or antimicrobial agents. STR1
- -
-
-
- Towards New Iron(III) Chelators: Synthesis and Complexing Ability of a Water-Soluble Tripodal Ligand Based on 2,2′-Dihydroxybiphenyl Subunits
-
A new water-soluble iron(III) sequestering agent has been designed. The tris-bidentate tripodal ligand consists of three 2,2′-dihydroxybiphenyl subunits connected via amide linkages at their meta (4-) positions to a framework of the "tren" type. The key step of the synthesis involves the coupling of suitably substituted monophenyl moieties in order to obtain the biphenyl precursor. The deprotonation constants of the ligand, and the formation and deprotonation constants of the FeIII complex have been determined from potentiometric and spectrophotometric measurements. The results are compared with those of a previously described homologous ligand in which the chelating subunits are attached to the tren framework via the ortho (3-) position of the biphenyl rather than the 4-position.
- Baret, Paul,Beaujolais, Virginie,Beguin, Claude,Gaude, Didier,Pierre, Jean-Louis,Serratrice, Guy
-
p. 613 - 619
(2007/10/03)
-
- Biologically Useful Chelators That Take Up Ca(2+) upon Illumination
-
Two approaches were explored toward the goal of synthesizing physiologically useful Ca(2+)-selective chelators whose Ca(2+) affinities increase markedly upon photolysis.In the first approach, the known Ca(2+)-selective chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) was masked with a variety of photoremovable protecting groups on one of its four carboxyl groups, reducing its affinity for Ca(2+) to ca. 1E5 M-1.Upon irradiation around 356 nm, free chelator with an affinity constant ca. 1E7 M-1 was regenerated but with very low quantumefficiencies (-1.Photochemical rearrangement of the diazoacetyl group converted it into an electron-donating carboxymethyl group, causing the Ca(2+) affinity to increase 30-fold to 1.4E7 M-1.The photolysis of Ca(2+)-free diazo-2 had a quantum efficiency with 365-nm light (λmax 370 nm, ε ca. 22000 M-1cm-1) of ca. 0.03 and generated the high-affinity chelator with rate constants of 2300 s-1 after a flash.Ca(2+) was then bound with association and dissociation rate constants of 8.0E8 M-1s-1 and 58 s-1, respectively.Diazo-2 was incorporated into rat fibroblasts either by microinjection or by incubation as the membrane-permeable, enzymatically labile tetrakis(acetoxymethyl) ester and, when flash-photolyzed, caused a drop in intracellular free to or below resting values of ca. 1E-7 M.An even larger increase in affinity(1600-fold) was obtained by substituting both phenyl rings of BAPTA with diazoacetyl substituents.Therefore, these chelators can be used to generate controlled fast decrements in intracellular free to mimic or ablate a host of important cellular responses, especially in nerve and muscle.
- Adams, S. R.,Kao, J. P. Y.,Tsien, R. Y.
-
p. 7957 - 7968
(2007/10/02)
-