- Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat
-
We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.
- Troelsen, Kathrin S.,Calder, Ewen D. D.,Skwarska, Anna,Sneddon, Deborah,Hammond, Ester M.,Conway, Stuart J.
-
p. 3691 - 3700
(2021/08/09)
-
- Palladium-catalyzed regio- And stereoselective access to allyl ureas/carbamates: Facile synthesis of imidazolidinones and oxazepinones
-
Typically, transition metal catalysis enforces the stereodefined outcome of a reaction. Here we disclose the palladium-catalyzed regio- and stereoselective access to allylic ureas/carbamates and their further exploitation to diverse cyclic structures under operationally simple reaction conditions. This protocol features palladium-catalyzed decarboxylative amidation of highly modular VECs with good to excellent yield, minimal waste production, wide substrate scope, and low catalyst loading. In follow-up chemistry, we demonstrated the debenzylation of vinylic imidazolidinones to N-hydroxycyclic ureas and regioselective derivatization towards the facile synthesis of halohydrins and oxiranes under mild reaction conditions in good to excellent yields. This journal is
- Banerjee, Prabal,Saha, Debarshi,Taily, Irshad Maajid
-
supporting information
p. 6564 - 6570
(2020/11/10)
-
- Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)
-
Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21percent oxygen) or physoxia (4–7.5percent oxygen) and hypoxia (2.0percent oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in 0.1percent oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.
- Calder, Ewen D. D.,Conway, Stuart J.,Folkes, Lisa K.,Hammond, Ester M.,Mistry, Ishna N.,Skwarska, Anna,Sneddon, Deborah
-
supporting information
(2020/04/24)
-
- Design, synthesis and evaluation of oxime-functionalized nitrofuranylamides as novel antitubercular agents
-
A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.
- Fan, Yi-Lei,Wu, Jian-Bing,Ke, Xing,Huang, Zhong-Ping
-
supporting information
p. 3064 - 3066
(2018/08/21)
-
- O-benzyl-N-(9-acridinyl)hydroxylamines
-
A series of O-benzyl-N-(9-acridinyl)hydroxylamines was prepared, isolated, and evaluated for biological activity using both thermal denaturation and MTT assays. Changes in the thermal denaturation temperature of genomic calf-thymus DNA ranged from +6.6 °C to +20.2 °C. MTT assays on SNB-19 glioblastoma cells provided biological activity that ranged from 17.4 μM to 33.2 μM. Both evaluation methods of biological activity indicate that substitution of the benzyl group by either electron-withdrawing or electron-donating groups provides a measureable benefit in these assays. The two assays agreed on the magnitude of the interaction for each substitution pattern.
- Johnson, Alyssa L.,Duncan, Nathan,Mosher, Michael D.
-
p. 139 - 148
(2018/06/27)
-
- O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1
-
Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.
- Malachowski, William P.,Winters, Maria,DuHadaway, James B.,Lewis-Ballester, Ariel,Badir, Shorouk,Wai, Jenny,Rahman, Maisha,Sheikh, Eesha,LaLonde, Judith M.,Yeh, Syun-Ru,Prendergast, George C.,Muller, Alexander J.
-
p. 564 - 576
(2016/01/09)
-
- NOVEL VASCULAR LEAKAGEAGE INHIBITOR
-
The present disclosure relates to a novel vascular leakage inhibitor. The novel vascular leakage inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, and enhances the cortical actin ring structure, thereby inhibiting vascular leakage. Accordingly, the vascular leakage inhibitor of the present invention can prevent or treat various diseases caused by vascular leakage. Since the vascular leakage inhibitor of the present invention is synthesized from commercially available or easily synthesizable pregnenolones, it has remarkably superior feasibility of commercial synthesis.
- -
-
Paragraph 0122
(2015/01/07)
-
- 4-Alkyloxyimino-cytosine nucleotides: Tethering approaches to molecular probes for the P2Y6 receptor
-
4-Alkyloxyimino derivatives of pyrimidine nucleotides display high potency as agonists of certain G protein-coupled P2Y receptors (P2YRs). In an effort to functionalize a P2Y6R agonist for fluorescent labeling, we probed two positions (N4 and γ-phosphate of cytidine derivatives) with various functional groups, including alkynes for click chemistry. Functionalization of extended imino substituents at the 4 position of the pyrimidine nucleobase of CDP preserved P2Y6R potency generally better than γ-phosphoester formation in CTP derivatives. Fluorescent Alexa Fluor 488 conjugate 16 activated the human P2Y6R expressed in 1321N1 human astrocytoma cells with an EC50 of 9 nM, and exhibited high selectivity for this receptor over other uridine nucleotide-activated P2Y receptors. Flow cytometry detected specific labeling with 16 to P2Y 6R-expressing but not to wild-type 1321N1 cells. Additionally, confocal microscopy indicated both internalized 16 (t1/2 of 18 min) and surface-bound fluorescence. Known P2Y6R ligands inhibited labeling. Theoretical docking of 16 to a homology model of the P2Y6R predicted electrostatic interactions between the fluorophore and extracellular portion of TM3. Thus, we have identified the N4-benzyloxy group as a structurally permissive site for synthesis of functionalized congeners leading to high affinity molecular probes for studying the P2Y6R.
- Jayasekara, P. Suresh,Barrett, Matthew O.,Ball, Christopher B.,Brown, Kyle A.,Kozma, Eszter,Costanzi, Stefano,Squarcialupi, Lucia,Balasubramanian, Ramachandran,Maruoka, Hiroshi,Jacobson, Kenneth A.
-
supporting information
p. 1156 - 1165
(2013/08/23)
-
- Design, synthesis and antifungal activities of novel pyrrole alkaloid analogs
-
A series of novel analogs of pyrrole alkaloid were designed and synthesized by a facile method and their structures were characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The structure of compound 2a was identified by 2D NMR including heteronuclear multiple-quantum coherence (HMQC), heteronuclear multiple-bond correlation (HMBC) and H-H correlation spectrometry (H-H COSY) spectra. Their antifungal activities against five fungi were evaluated, and the results indicated that some of the title compounds showed moderate fungicidal activities in vitro against Alternaria solani, Cercospora arachidicola, Fusarium omysporum, Gibberella zeae and Physalospora piricola at the dosage of 50 μg mL -1. Compound 2a and 3a exhibited good activities against P. piricola at low dosage.
- Wang, Ming-Zhong,Xu, Han,Liu, Tuan-Wei,Feng, Qi,Yu, Shu-Jing,Wang, Su-Hua,Li, Zheng-Ming
-
experimental part
p. 1463 - 1472
(2011/05/04)
-
- Photoinduced electron-transfer-promoted redox fragmentation of N-alkoxyphthalimides
-
A new photoinduced electron-transfer-promoted redox fragmentation of N-alkoxyphthalimides has been developed. Mechanistic experiments have established that this reaction proceeds through a unique concerted intramolecular fragmentation process. This distinctive mechanism imparts many synthetic advantages, which are highlighted in the redox fragmentation of various heterocyclic substrates.
- Zlotorzynska, Maria,Sammis, Glenn M.
-
supporting information; experimental part
p. 6264 - 6267
(2012/01/15)
-
- 2-[(arylmethoxy)imino]imidazolidines with potential biological activities
-
A series of 2-[(arylmethoxy)imino]imidazolidines was synthesized by reacting 2-chloro-4,5-dihydroimidazole with corresponding O- arylmethylhydroxylamines and evaluated for their α1-, α2-adrenergic and imidazoline I1, I2 receptor binding affinities. The most potent 2-[(naphthalen-1-ylmethoxy)imino] imidazolidine showed a high selectivity and good affinity for the [ 3H]prazosin-labeled α1-adrenoceptors (Ki = 107 nM). Representative compounds of this series were also tested in vivo for possible circulatory effects in rats after intravenous administration.
- Saczewski, Jaroslaw,Hudson, Alan L.,Rybczynska, Apolonia
-
experimental part
p. 671 - 680
(2010/07/04)
-
- NON-STEROIDAL COMPOUNDS
-
The present invention relates to non-steroidal compounds useful in the treatment of inflammatory conditions and pharmaceutical compositions comprising them. A representative example of these compounds is formula (III).
- -
-
Page/Page column 41-42
(2008/12/08)
-
- Synthesis and fungicidal activity of macrolactams and macrolactones with an oxime ether side chain
-
Three series of novel macrolactams and macrolactones - 12-alkoxyimino- tetradecanlactam, 12-alkoxyiminopentadecanlactam, and 12-alkoxyiminodecanlactone derivatives (7A, 7B, and 7C) - were synthesized from corresponding 12-oxomacrolactams and 12-oxomacrolactone. Their structures were confirmed by 1H NMR and elemental analysis. The Z and E isomers of 7A and 7B were separated, and their configurations were determined by 1H NMR. These compounds showed fair to excellent fungicidal activities against Rhizoctonia solani Kuehn. It is interesting that the Z and E isomers of most of the compounds have quite different fungicidal activities. The fact that the compounds have a gradual increase of fungicidal activity in the order of 7A, 7C, and 7B indicated that the macrocyclic derivatives with a hydrogen-bonding acceptor (=N-O-) and a hydrogen-bonding donor (-CONH-) on the ring, and a three methylenes distance (CH2CH2CH2) between these two functional groups, exhibited the best fungicidal activity. The bioassay also showed that 7B not only has good fungicidal activity but also may have a broad spectrum of fungicidal activities.
- Huang, Jia-Xing,Jia, Yue-Mei,Liang, Xiao-Mei,Zhu, Wei-Juan,Zhang, Jian-Jun,Dong, Yan-Hong,Yuan, Hui-Zu,Qi, Shu-Hua,Wu, Jin-Ping,Chen, Fu-Heng,Wang, Dao-Quan
-
experimental part
p. 10857 - 10863
(2009/11/30)
-
- 1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines, a novel class of NR1/2B subtype selective NMDA receptor antagonists
-
Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.
- Alanine, Alexander,Bourson, Anne,Buettelmann, Bernd,Gill, Ramanjit,Heitz, Marie-Paule,Mutel, Vincent,Pinard, Emmanuel,Trube, Gerhard,Wyler, Rene
-
p. 3155 - 3159
(2007/10/03)
-
- TOTAL SYNTHESIS OF ANTITUMOR AGENT AT-125, (αS,5S)-α-AMINO-3-CHLORO-4,5-DIHYDRO-5-ISOXAZOLEACETIC ACID
-
A short and efficient total synthesis of racemic AT-125 and its racemic threo isomer proceeds via an intramolecular Michael cyclization of a protected α,β-dehydroglutamic acid γ-hydroxamate.Separation of diastereomers and deprotection to racemic AT-125 followed by enzymatic resolution of the N-chloroacetamide with hog-kidney acylase provides the natural αS,5S isomer.
- Baldwin, Jack E.,Cha, Jin K.,Kruse, Lawrence I.
-
p. 5241 - 5260
(2007/10/02)
-