- Water-Proton Relaxivities of Radical Nanoparticles Self-Assembled via Hydration or Dehydration Processes
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Nanoparticles capable of accumulating in tumor tissues are promising materials for tumor imaging and therapy. In this study, two radical nanoparticles (RNPs), denoted as 1 and 2, composed of self-assembled ureabenzene derivatives possessing one or two amp
- Morishita, Kosuke,Okamoto, Yuna,Murayama, Shuhei,Usui, Kazuteru,Ohashi, Eriko,Hirai, Go,Aoki, Ichio,Karasawa, Satoru
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- Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer
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Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.
- Akwii, Racheal,Alvina, Karina,Ashraf-Uz-Zaman, Md,Farshbaf, Mohammad Jodeiri,German, Nadezhda A.,Kallem, Raja Reddy,Mikelis, Constantinos M.,Putnam, William,Sajib, Md Sanaullah,Shahi, Sadisna,Trippier, Paul C.,Wang, Wei,Zhang, Ruiwen
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- Electrochemically Enabled Intramolecular Aminooxygenation of Alkynes via Amidyl Radical Cyclization
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An electrochemical synthesis of oxazol-2-ones and imidazol-2-ones has been developed via 5-exo-dig cyclization of propargylic carbamates- and ureas-derived amidyl radicals. The electrosynthesis relies on the dual function of 2,2,6,6-tetramethylpiperidin- 1-yl)oxyl (TEMPO) as a redox mediator for amidyl radical formation and an oxygen atom donor. The reactions are conducted under mild conditions using a simple setup and provide convenient access to functionalized oxazol-2-ones and imidazol-2-ones from readily available materials.
- Hou, Zhong-Wei,Xu, Hai-Chao
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supporting information
p. 394 - 398
(2020/03/04)
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- Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus
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Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
- Ruan, Banfeng,Zhang, Yuezhou,Tadesse, Solomon,Preston, Sarah,Taki, Aya C.,Jabbar, Abdul,Hofmann, Andreas,Jiao, Yaqing,Garcia-Bustos, Jose,Harjani, Jitendra,Le, Thuy Giang,Varghese, Swapna,Teguh, Silvia,Xie, Yiyue,Odiba, Jephthah,Hu, Min,Gasser, Robin B.,Baell, Jonathan
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supporting information
(2020/02/04)
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- Electrochemical C?H/N?H Functionalization for the Synthesis of Highly Functionalized (Aza)indoles
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Indoles and azaindoles are among the most important heterocycles because of their prevalence in nature and their broad utility in pharmaceutical industry. Reported herein is an unprecedented noble-metal- and oxidant-free electrochemical method for the coupling of (hetero)arylamines with tethered alkynes to synthesize highly functionalized indoles, as well as the more challenging azaindoles.
- Hou, Zhong-Wei,Mao, Zhong-Yi,Zhao, Huai-Bo,Melcamu, Yared Yohannes,Lu, Xin,Song, Jinshuai,Xu, Hai-Chao
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supporting information
p. 9168 - 9172
(2016/08/05)
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- Mono- and triiodophenyl isocyanate as radiopacifying agents for methacrylate-based copolymers; Biocompatibility and non-toxicity
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New radiopaque acrylic copolymers were prepared via the copolymerization of methyl methacrylate (MMA) and acrylic acid (AA). The copolymers were made radiopaque through the reaction of carboxylic acid groups with 4-iodophenyl isocyanate and 3,4,5-triiodop
- Shiralizadeh, Saeed,Nasr-Isfahani, Hossein,Keivanloo, Ali,Bakherad, Mohammad
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p. 110400 - 110408
(2016/11/30)
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- Rhenium-catalyzed C-H aminocarbonylation of azobenzenes with isocyanates
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The first C-H aminocarbonylation of azobenzenes with isocyanates is achieved by using rhenium-catalysis, which provides an expedient and atom-economical access to varied o-azobenzamides from readily available starting materials. The reaction efficiency can be enhanced by the catalytic use of sodium acetate via accelerated C-H bond activation.
- Geng, Xiaoyu,Wang, Congyang
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supporting information
p. 7619 - 7623
(2015/07/15)
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- Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors
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A number of 1,2-benzisothiazol-3-one derivatives were prepared through structural modification of the original compound from high-throughput screening. Some analogues (e.g., 6b, 6r, 6s and 6w) were identified as novel and potent caspase inhibitors with IC50 of nanomolar. Structure-activity relationship (SAR) studies for caspase-3 inhibition were evaluated in vitro. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The present small molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis.
- Liu, Dazhi,Tian, Zhen,Yan, Zhihui,Wu, Lixin,Ma, Yan,Wang, Quan,Liu, Wei,Zhou, Honggang,Yang, Cheng
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p. 2960 - 2967
(2013/07/28)
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- 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: Structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain
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1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl) piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl) urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.
- Rose, Tristan E.,Morisseau, Christophe,Liu, Jun-Yan,Inceoglu, Bora,Jones, Paul D.,Sanborn, James R.,Hammock, Bruce D.
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supporting information; experimental part
p. 7067 - 7075
(2010/12/25)
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- Comparison of base-promoted and self-catalyzed conditions in the synthesis of isocyanates from amines using triphosgene
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Comparison of base-promoted and self-catalyzed conditions for the synthesis of isocyanates from amines and triphosgene shows no advantage in using an amine base in the majority of cases. The workup and isolation of the product is simplified under base-free conditions. Yields of between 50 and 90% after distillation were common. Only acid-sensitive substrates need a base catalyst. Copyright Taylor & Francis Group, LLC.
- Charalambides, Yiannis C.,Moratti, Stephen C.
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p. 1037 - 1044
(2007/10/03)
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- Linking metal centres with diimido ligands: Synthesis, electronic and molecular structure and electrochemistry of organometallic ditungsten complexes [{WCl2(Ph2PMe)2(CO)}2(N-X-N)] (X = π-conjugated organic)
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Tungsten(IV) diimido-bridged complexes [{WCl2(Ph2PMe)2(CO)}(μ-N-X-N)] have been prepared via oxidative addition of diisocyanates to two equivalents of [WCl2(Ph2PMe)4]. para-Substituted monoimido complexes [WCl2(Ph2PMe)2(CO)(NC6H 4X-p)] (X = I, Br or C≡CPh) have also been prepared but attempts to couple the X = I complex as a route to diimido-bridged complexes were unsuccessful. All complexes are air-stable crystalline solids and five diimido (N-X-N = p-NC6H4N, p-N-o-MeC6H3N, p-N(o-MeOC6H3C6H3OMe-o)N, 1,5-NC10H6N or m-NC6H4N) and one monoimido complex (X = I) have been characterised crystallographically. All show the same gross structural features, namely a trans arrangement of phosphines and cis chlorides. The central aryl ring generally lies approximately in the Cl2(CO) plane (torsional angles 4.1-26.1°) except for one complex in which the ring lies almost perpendicular to this (torsional angle 80.2°). A series of density functional calculations conducted on model mono- and di-imido tungsten-(VI) and -(V) compounds indicated that the most stable aryl ring orientation is perpendicular to the plane containing the trans phosphines, i.e. as found in all cases except one (N-X-N = p-NC6H4N). The anomaly in the latter may be due to cocrystallisation with chlorobenzene. In order to assess the degree of communication between the tungsten(IV) centres through the highly π-conjugated diimido linkages, electrochemical studies have been carried out. All diimido-bridged complexes show two closely spaced oxidative processes at low temperature indicative of weak electronic communication. The reductive chemistry of the para-phenylene bridged complexes is different from other diimido complexes, displaying two closely spaced reductive processes. Spectro-electrochemical studies have also been carried out on N-X-N = p-NC6H4N, oxidation at +1.2 V leading to CO loss. In order to gain further insight into the nature of the electronic communication between metal centres density functional calculations were carried out and were generally in agreement with the electrochemical results, suggesting that there is at best a weak interaction between the metal centres in these π-conjugated diimido-bridged complexes.
- Hogarth, Graeme,Humphrey, David G.,Kaltsoyannis, Nikolas,Kim, Woo-Sung,Lee, Mo-Yin,Norman, Tim,Redmond, Simon P.
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p. 2705 - 2723
(2007/10/03)
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- [125I]iodoproxyfan and related compounds: a reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor.
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The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.
- Stark,Purand,Huels,Ligneau,Garbarg,Schwartz,Schunack
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p. 1220 - 1226
(2007/10/03)
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- Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity
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The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4- yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log K(i) values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Stark, Holger,Purand, Katja,Ligneau, Xavier,Rouleau, Agnès,Arrang, Jean-Michel,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
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p. 1157 - 1163
(2007/10/03)
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- Quantitative Structure-Activity Relationships of Insecticidal Pyrazolines
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Methyl 3-(4-chlorophenyl)-4-methyl-1--2-pyrazoline-4-carboxylates and related compounds were prepared. Their convulsant activity was determined as the minimum dose required to bring about the symptom within 1 h after injection against male adult American cockroaches, Periplaneta americana (L.). Insecticidal activity with metabolic inhibitors for oxidation and hydrolysis was measured 24 h after injection of the test compounds. Variations in each of the activities were analysed by using physicochemical substituent parameters and regression analysis. The findings indicated that the greater the hydrophobicity and the more the electron-withdrawing property of the substituents, the higher were the activities. Variations in each of the two activities were parabolically related to the STERIMOL width parameter with an optimum value of about zero.
- Hasan, Riaz,Nishimura, Keiichiro,Ueno, Tamio
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p. 291 - 298
(2007/10/03)
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