5-(3-Chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide

CID-2011756 is a novel and potent inhibitor of protein kinase D1 (PKD1), one of three PKD isoforms of a novel family of serine/threonine kinases involved in cell proliferation, survival, invasion and protein transport, with a value of 50% inhibition concentration IC₅₀ of 3.2 μM in vitro. CID-2011756 also exhibits pan-PKD inhibitory effects that ATP-competitively inhibits PKD2 and PDK3 with values of IC₅₀ of 0.6 μM and 0.7 μM respectively. Study results have shown that CID-2011756 is a cell active PKD1 inhibitor that concentration-dependently inhibits phorbolester-induced endogenous PKD1 activation in LNCap prostate cancer cells with a value of half maximal effective concentration EC₅₀ of 10 μM.

Reference

Sharlow ER, Mustata Wilson G, Close D, Leimgruber S, Tandon M, Reed RB, Shun TY, Wang QJ, Wipf P, Lazo JS. Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. PLoS One. 2011;6(10):e25134.

Profiling of hydroxycinnamoylquinic acids in plant extracts using in-source CID fragmentation.[Pubmed:27591562]

J Mass Spectrom. 2016 Dec;51(12):1130-1145.

Hydroxycinnamoylquinic acids (HCQAs) are a major class of phenolic plant secondary metabolites, belonging to the chlorogenic acid family. Various health-beneficial properties of HCQAs have been shown, which has drawn interest for HCQA profiling in plants of human consumption. However, this task remains challenging, because several isomeric HCQAs can be present in the sample with identical molecular formulae and the limited availability of reference standards poses additional challenges to their identification. In the present work, a high performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry (HPLC-ESI-Q/TOF-MS) method accompanied with an effective data filtering protocol is presented, which is shown to be suitable for the identification of HCQAs in plant materials in a non-targeted manner. Both collision-induced dissociation (CID) fragmentation performed in a collision cell and in-source (CID) fragmentation were used to produce accurate mass fragments. It was shown that fragmentation characteristics required for identification of regio-isomers of HCQAs can be achieved with in-source CID fragmentation, enabling the use of a single-stage MS system with in-source fragmentation for convincing identification of HCQAs. Based on a thorough validation of identified HCQA compounds using coffee bean extracts as reference samples, comprehensive profiling of HCQAs in two apricot (Prunus armeniaca L.) genotypes ('Preventa' and 'Gonci magyarkajszi') was carried out for the first time and the following 10 HCQAs were shown to be present in apricot fruit: 3-caffeoylquinic acid (CQA), cis-3-CQA, 4-CQA, 5-CQA, cis-5-CQA, 3,5-diCQA, 3-p-coumaroylquinic acid (pCoQA), 4-pCoQA, 3-feruloylquinic acid (FQA) and cis-3-FQA. Copyright (c) 2016 John Wiley & Sons, Ltd. HIGHLIGHTS: An HPLC-ESI-Q/TOF-MS method suitable for the identification of hydroxycinnamoyilquinic acids (HCQAs) in plant material in a non-targeted manner was developed. Single-stage, high-resolution MS system with in-source fragmentation was shown to be suitable for convincing identification of HCQAs. Comprehensive profiling of HCQAs in two apricot (Prunus armeniaca L.) genotypes was carried out for the first time. Copyright (c) 2016 John Wiley & Sons, Ltd.

Analysis of matrix-assisted laser desorption/ionization quadrupole time-of-flight collision-induced dissociation spectra of simple precursor ions and isobaric oligosaccharide ion mixtures based on product ion intensities and pattern recognition.[Pubmed:28299859]

Rapid Commun Mass Spectrom. 2017 May 30;31(10):873-885.

RATIONALE: Qualitative analysis of glycomic tandem mass spectrometry (MS/MS) data based on m/z values of product ions alone is widely used, and often sufficient for analysis of single analytes. However, most complex glycomic mixtures contain multiple isobaric oligosaccharides, in which case this approach is often limited. Here we show how ion intensity information can be used in order to enhance MS/MS data analysis, and extract both qualitative and semiquantitative information from complex glycomic MS/MS datasets. METHODS: A matrix-assisted laser desorption/ionization quadrupole time-of-flight (MALDI QTOF) mass spectrometer was used in this study. We compared the intensities of product ions within a single product ion series, determined by their length, across the whole glycomic MS/MS dataset. In order to detect discernable patterns, the intensity data was normalized to the intensity of each product ion within the series. In most cases, normalized data yielded easily discernable patterns, relevant either for analysis of specific glycomic structure types, or mechanistic MS studies. RESULTS: We used our approach on a glycomic sample consisting of human milk oligosaccharides. The approach yielded useful results for both qualitative and semiquantitative analyses. All normalizations performed were not equally rich in information and the information content of generated tables was not possible to predict. These analyses were shown to be independent of instrument manufacturer. CONCLUSIONS: Our approach enabled more detailed qualitative analysis of MS/MS spectra of precursor ions containing isobaric oligosaccharide structures. While limited semiquantitative information could be extracted from the raw data as well, the accuracy of this method should be significantly enhanced when standard calibration mixtures can be prepared. Copyright (c) 2017 John Wiley & Sons, Ltd.

Gas-Phase Fragmentation Behavior of Oxidized Prenyl Peptides by CID and ETD Tandem Mass Spectrometry.[Pubmed:27785692]

J Am Soc Mass Spectrom. 2017 Apr;28(4):704-707.

Farnesylation and geranylgeranylation are the two types of prenyl modification of proteins. Prenylated peptides are highly hydrophobic and their abundances in biological samples are low. In this report, we studied the oxidized prenylated peptides by electrospray ionization mass spectrometry and identified them by collision-induced dissociation (CID) and electron-transfer dissociation (ETD) tandem mass spectrometry. Modified prenyl peptides were generated utilizing strong and low strength oxidizing agents to selectively oxidize and epoxidize cysteine sulfur and prenyl side chain. We selected three peptides with prenyl motifs and synthesized their prenylated versions. The detailed characteristic fragmentations of oxidized and epoxidized farnesylated and geranylgeranylated peptides were studied side by side with two popular fragmentation techniques. CID and ETD mass spectrometry clearly distinguished the modified version of these peptides. ETD mass spectrometry provided sequence information of the highly labile modified prenyl peptides and showed different characteristic fragmentations compared with CID. A detailed fragmentation of modified geranylgeranylated peptides was compared by CID and ETD mass spectrometry for the first time. Graphical Abstract .

Modeling collision energy transfer in APCI/CID mass spectra of PAHs using thermal-like post-collision internal energy distributions.[Pubmed:27802636]

J Chem Phys. 2016 Oct 28;145(16):164311.

The internal energy transferred when projectile molecular ions of naphthalene collide with argon gas atoms was extracted from the APCI-CID (atmospheric-pressure chemical ionization collision-induced dissociation) mass spectra acquired as a function of collision energy. Ion abundances were calculated by microcanonical integration of the differential rate equations using the Rice-Ramsperger-Kassel-Marcus rate constants derived from a UB3LYP/6-311G+(3df,2p)//UB3LYP/6-31G(d) fragmentation mechanism and thermal-like vibrational energy distributions pME,Tchar. The mean vibrational energy excess of the ions was characterized by the parameter Tchar ("characteristic temperature"), determined by fitting the theoretical ion abundances to the experimental breakdown graph (a plot of relative abundances of the ions as a function of kinetic energy) of activated naphthalene ions. According to these results, the APCI ion source produces species below Tchar = 1457 K, corresponding to 3.26 eV above the vibrational ground state. Subsequent collisions heat the ions up further, giving rise to a sigmoid curve of Tchar as a function of Ecom (center-of-mass-frame kinetic energy). The differential internal energy absorption per kinetic energy unit (dEvib/dEcom) changes with Ecom according to a symmetric bell-shaped function with a maximum at 6.38 +/- 0.32 eV (corresponding to 6.51 +/- 0.27 eV of vibrational energy excess), and a half-height full width of 6.30 +/- 1.15 eV. This function imposes restrictions on the amount of energy that can be transferred by collisions, such that a maximum is reached as kinetic energy is increased. This behavior suggests that the collisional energy transfer exhibits a pronounced increase around some specific value of energy. Finally, the model is tested against the CID mass spectra of anthracene and pyrene ions and the corresponding results are discussed.

Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity.[Pubmed:21998636]

PLoS One. 2011;6(10):e25134.

Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC(50)s for these eleven compounds ranged in potency from 0.4 to 6.1 microM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-Chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien -1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target.

CID 2011756 is an ATP competitive PKD inhibitor, with an IC50 of 3.2 µM for PKD1 in cell free assay, and also shows cellular pan-PKD inhibitory activity against PKD2 and PKD3 (IC50, 0.6 and 0.7 µM, respectively). CID 2011756 also has antitumor activity.

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