22955-88-0Relevant academic research and scientific papers
Discovery of 4,6-bis(2-((E)-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity
Russell, Cecilia C.,Stevens, Andrew,Young, Kelly A.,Baker, Jennifer R.,McCluskey, Siobhann N.,Khazandi, Manouchehr,Pi, Hongfei,Ogunniyi, Abiodun,Page, Stephen W.,Trott, Darren J.,McCluskey, Adam
, p. 896 - 907 (2019)
Robenidine (E)-N′-((E)-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant Staphyoccoccus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL?1. Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2-NH2 triazine moiety saw a 10-fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4-BrPh and 4-CH3Ph with MIC values of 2 and 4 μg mL?1, against MRSA and VRE respectively, are promising candidates for future development.
Phosphate-, Phosphite-, Ylide-, and Phosphonate-Terminated Dendrimers
Prevote, Delphine,Caminade, Anne-Marie,Majoral, Jean Pierre
, p. 4834 - 4841 (1997)
Many types of tri- and tetracoordinated phosphorus derivatives have been grafted on the surface of dendrimers, starting from aldehyde terminal functions. Depending on the solubility of the resulting phosphorylated dendrimers, these experiments have been carried out on generation 1 (six end groups) for phosphate- (4-[G1]), phosphinite- (6-[G1]), and ylide-terminated (11-[G1]) dendrimers and up to generation 5 (96 end groups) for aminophosphate- (8-[G1], 8-[G5]), aminophosphite (10-[G1], 10-[G5]), and functionalized phosphonate-terminated (14-[G1]-14-[G5], 15-[G1], 15-[G5], 17-[G1], 19-[G1], 19-[G5]) dendrimers. Most of the phosphonate-terminated dendrimers present an unexpected long-range phosphorus - phosphorus coupling constant through seven bonds (3,8 7VPP 4.5 Hz).
Quinone Methide-Based Organophosphate Hydrolases Inhibitors: Trans Proximity Labelers versus Cis Labeling Activity-Based Probes
Dubovetskyi, Artem,Cherukuri, Kesava Phaneendra,Ashani, Yacov,Meshcheriakova, Anna,Reuveny, Eitan,Ben-Nissan, Gili,Sharon, Michal,Fumagalli, Laura,Tawfik, Dan S.
, p. 894 - 903 (2020/12/09)
Quinone methide (QM) chemistry is widely applied including in enzyme inhibitors. Typically, enzyme-mediated bond breaking releases a phenol product that rearranges into an electrophilic QM that in turn covalently modifies protein side chains. However, the factors that govern the reactivity of QM-based inhibitors and their mode of inhibition have not been systematically explored. Foremost, enzyme inactivation might occur in cis, whereby a QM molecule inactivates the very same enzyme molecule that released it, or by trans if the released QMs diffuse away and inactivate other enzyme molecules. We examined QM-based inhibitors for enzymes exhibiting phosphoester hydrolase activity. We tested different phenolic substituents and benzylic leaving groups, thereby modulating the rates of enzymatic hydrolysis, phenolate-to-QM rearrangement, and the electrophilicity of the resulting QM. By developing assays that distinguish between cis and trans inhibition, we have identified certain combinations of leaving groups and phenyl substituents that lead to inhibition in the cis mode, while other combinations gave trans inhibition. Our results suggest that cis-acting QM-based substrates could be used as activity-based probes to identify various phospho- and phosphono-ester hydrolases, and potentially other hydrolases.
Novel ratiometric fluorescent probe for real-time detection of alkaline phosphatase and its application in living cells
Chen, Shijun,Chen, Xiangzhu,Hou, Shicong,Huang, Xiaoqian,Ma, Xiaodong,Wang, Lin,Zhang, Xueyan
, (2021/05/27)
A novel ratiometric fluorescent probe has been developed through a simple synthetic route for the detection of alkaline phosphatase(ALP) in aqueous media and for fluorescence imaging in living cells. The introduction of a spontaneous-degradation spacer in
Novel conjugated unsaturated ketones with submicromolar potencies towards some leukemic and colon cancer cells
Balzarini, Jan,Das, Swagatika,Das, Umashankar,Dimmock, Jonathan R.,Dimmock, Stephen G.,Inci Gul, H.
, p. 430 - 438 (2019/07/12)
Background: Cancer continues to be the major health burden worldwide. There is an urgent need for the development of novel antineoplastic compounds to treat this devastating condition. Various alkylating anticancer drugs have been employed in the clinic for treating cancers. Unsaturated conjugated ketones are a group of alkylators which are of significant interest as potent antineoplastic agents. Objective: The goal of this study is to discover unsaturated conjugated ketones which are novel potent cytotoxins displaying growth-inhibitory properties towards neoplasms and also to serve as cytotoxic warheads in drug development. Methods: A variety of 3,5-bis (benzylidene)-4-piperidones 2a-n were synthesized and evaluated against a number of neoplastic cell lines. The short-term neurotoxicity of 2a-k, n was evaluated in mice by i.p. administration using doses level of 30, 100 and 300 mg/kg. Statistical correlations for determining structure-activity relationships were performed using an SPSS software. Results: A number of compounds display cytotoxic potencies in the region of 10-7 to 10-8 M and some of the structural features contributing to the cytotoxicity were identified. Compounds 2a-d, 2h demonstrated substantially higher cytotoxic potencies compared to melphalan and 5- fluorouracil against a panel of leukemic and colon cancer cell lines. These lead cytotoxins comply with drug-likeness properties. In general, the antineoplastics 2 are well tolerated in mice using a short-term neurotoxicity screening. Conclusion: In general, this group of compounds comprises excellent cytotoxic agents, which warrant their further development as cytotoxic warheads.
Transition State Analysis of the Reaction Catalyzed by the Phosphotriesterase from Sphingobium sp. TCM1
Bigley, Andrew N.,Xiang, Dao Feng,Narindoshvili, Tamari,Burgert, Charlie W.,Hengge, Alvan C.,Raushel, Frank M.
, p. 1246 - 1259 (2019/03/07)
Organophosphorus flame retardants are stable toxic compounds used in nearly all durable plastic products and are considered major emerging pollutants. The phosphotriesterase from Sphingobium sp. TCM1 (Sb-PTE) is one of the few enzymes known to be able to hydrolyze organophosphorus flame retardants such as triphenyl phosphate and tris(2-chloroethyl) phosphate. The effectiveness of Sb-PTE for the hydrolysis of these organophosphates appears to arise from its ability to hydrolyze unactivated alkyl and phenolic esters from the central phosphorus core. How Sb-PTE is able to catalyze the hydrolysis of the unactivated substituents is not known. To interrogate the catalytic hydrolysis mechanism of Sb-PTE, the pH dependence of the reaction and the effects of changing the solvent viscosity were determined. These experiments were complemented by measurement of the primary and secondary 18-oxygen isotope effects on substrate hydrolysis and a determination of the effects of changing the pKa of the leaving group on the magnitude of the rate constants for hydrolysis. Collectively, the results indicated that a single group must be ionized for nucleophilic attack and that a separate general acid is not involved in protonation of the leaving group. The Br?nsted analysis and the heavy atom kinetic isotope effects are consistent with an early associative transition state with subsequent proton transfers not being rate limiting. A novel binding mode of the substrate to the binuclear metal center and a catalytic mechanism are proposed to explain the unusual ability of Sb-PTE to hydrolyze unactivated esters from a wide range of organophosphate substrates.
Cellular protection of SNAP-25 against botulinum neurotoxin/A: Inhibition of thioredoxin reductase through a suicide substrate mechanism
Seki, Hajime,Xue, Song,Pellett, Sabine,?ilhár, Peter,Johnson, Eric A.,Janda, Kim D.
supporting information, p. 5568 - 5575 (2016/06/01)
Botulium neurotoxins (BoNTs) are among the most lethal toxins known to man. They are comprised of seven serotypes with BoNT/A being the most deadly; yet, there is no approved therapeutic for their intoxication or one that has even advanced to clinical trials. Botulinum neurotoxicity is ultimately governed through light chain (LC) protease SNARE protein cleavage leading to a loss of neurotransmitter release. Pharmacological attempts to ablate BoNT/A intoxication have sought to either nullify cellular toxin entry or critical biochemical junctions found within its intricate mechanism of action. In these regards, reports have surfaced of nonpeptidic small molecule inhibitors, but few have demonstrated efficacy in neutralizing cellular toxicity, a key prerequisite before rodent lethality studies can be initiated. On the basis of a lead discovered in our BoNT/A cellular assay campaign, we investigated a family of N-hydroxysuccinimide inhibitors grounded upon structure activity relationship (SAR) fundamentals. Molecules stemming from this SAR exercise were theorized to be protease inhibitors. However, this proposition was overturned on the basis of extensive kinetic analysis. Unexpectedly, inhibitor data pointed to thioredoxin reductase (TrxR), an essential component required for BoNT protease translocation. Also unforeseen was the inhibitors' mechanism of action against TrxR, which was found to be brokered through a suicide-mechanism utilizing quinone methide as the inactivating element. This new series of TrxR inhibitors provides an alternative means to negate the etiological agent responsible for BoNT intoxication, the LC protease.
Organelle-specific detection of phosphatase activities with two-photon fluorogenic probes in cells and tissues
Li, Lin,Ge, Jingyan,Wu, Hao,Xu, Qing-Hua,Yao, Shao Q.
experimental part, p. 12157 - 12167 (2012/09/22)
Two-photon fluorescence microscopy (TPFM) provides key advantages over conventional fluorescence imaging techniques, namely, increased penetration depth, lower tissue autofluorescence and self-absorption, and reduced photodamage and photobleaching and therefore is particularly useful for imaging deep tissues and animals. Enzyme-detecting, small molecule probes provide powerful alternatives over conventional fluorescent protein (FP)-based methods in bioimaging, primarily due to their favorable photophysical properties, cell permeability, and chemical tractability. In this article, we report the first fluorogenic, small molecule reporter system (Y2/Y1) capable of imaging endogenous phosphatase activities in both live mammalian cells and Drosophila brains. The one- and two-photon excited photophysical properties of the system were thoroughly investigated, thus confirming the system was indeed a suitable Turn-ON fluorescence pair for TPFM. To our knowledge, this is the first enzyme reporting two-photon fluorescence bioimaging system which was designed exclusively from a centrosymmetric dye possessing desirable two-photon properties. By conjugation of our reporter system to different cell-penetrating peptides (CPPs), we were able to achieve organelle- and tumor cell-specific imaging of phosphatase activities with good spatial and temporal resolution. The diffusion problem typically associated with most small molecule imaging probes was effectively abrogated. We further demonstrated this novel two-photon system could be used for imaging endogenous phosphatase activities in Drosophila brains with a detection depth of >100 μm.
Dynamic substrate enhancement for the identification of specific, second-site-binding fragments targeting a set of protein tyrosine phosphatases
Schmidt, Marco F.,Groves, Matthew R.,Rademann, Joerg
experimental part, p. 2640 - 2646 (2012/05/07)
Protein tyrosine phosphatases (PTPs) are key regulators in living systems and thus are attractive drug targets. The development of potent, selective PTP inhibitors has been a difficult challenge mainly due to the high homology of the phosphotyrosine substrate pockets. Here, a strategy of dynamic substrate enhancement is described targeting the secondary binding sites of PTPs. By screening four different PTPs from bacterial (MptpA) and human origin (PTP1B, HePtp, Shp2) with this assay, specific fragments were identified. One highly specific fragment that binds to the secondary site of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) was characterized in order to validate the assay concept. Finally by covalently linking the secondary fragment to a phosphotyrosine mimetic, a moderately active but highly specific inhibitor of MptpA was obtained.
WATER-SOLUBLE SHPS AS NOVEL ALKYLATING AGENTS
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Page 9, (2010/02/09)
The present invention relates to compounds according to the structure (I): Where R is —CH3 or —CH2CH2Cl; R′ is C1-C7 alkyl or —CH2CH2Cl; R2 or R4 is OPOsub
