- (E)-2-Cyano-3-(1H-Indol-3-yl)-N-phenylacrylamide, a hybrid compound derived from indomethacin and paracetamol: Design, synthesis and evaluation of the anti-inflammatory potential
-
The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p -1) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2-6 h. In addition, there was no significant inhibition of PGE2, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.
- Albino, Sonaly,Espírito-Santo, Renan,Lima, Maria,Moura, Ricardo,Santos, Vanda,Silva, Jamire,Silva, Pablo,Villarreal, Cristiane,de Almeida, Maria
-
-
Read Online
- Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma
-
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
- Liang, Xuewu,Sun, Chenxia,Li, Chunpu,Yu, Haolan,Wei, Xiaohui,Liu, Xuyi,Bao, Wei,Shi, Yuqiang,Sun, Xiaochen,Khamrakulov, Mirzadavlat,Yang, Chenghua,Liu, Hong
-
p. 9217 - 9237
(2021/07/20)
-
- Synthesis and Docking Study of Novel Pyranocoumarin Derivatives
-
Abstract: A new series of fused tricyclic coumarin derivatives were designed, synthesized by a simple and convenient method, starting from 4-hydroxycoumarin and virtually screened by molecular docking on the target protein 3FRZ (PDB ID: 3FRZ), a HCV RNA-dependent RNA polymerase, for potency against hepatitis C virus (HCV). Efficient binding to the target protein was found for most of the synthesized compounds.
- Karteek, S. Durga,Reddy, A. Gopi,Tej, M. Bhuvan,Rao, M. V. Basaveswara
-
p. 272 - 282
(2021/04/02)
-
- Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones
-
The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.
- Wen, Li-Rong,Wang, Ning-Ning,Du, Wu-Bo,Ma, Qiang,Zhang, Lin-Bao,Li, Ming
-
supporting information
p. 2895 - 2900
(2021/04/14)
-
- Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
-
Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.
- Gerndt, Susanne,Chen, Cheng-Chang,Chao, Yu-Kai,Yuan, Yu,Burgstaller, Sandra,Rosato, Anna Scotto,Krogsaeter, Einar,Urban, Nicole,Jacob, Katharina,Nguyen, Ong Nam Phuong,Miller, Meghan T.,Keller, Marco,Vollmar, Angelika M.,Gudermann, Thomas,Zierler, Susanna,Schredelseker, Johann,Schaefer, Michael,Biel, Martin,Malli, Roland,Wahl-Schott, Christian,Bracher, Franz,Patel, Sandip,Grimm, Christian
-
-
- Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
-
Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).
- Endo, Satoshi,Oguri, Hiroaki,Segawa, Jin,Kawai, Mina,Hu, Dawei,Xia, Shuang,Okada, Takuya,Irie, Katsumasa,Fujii, Shinya,Gouda, Hiroaki,Iguchi, Kazuhiro,Matsukawa, Takuo,Fujimoto, Naohiro,Nakayama, Toshiyuki,Toyooka, Naoki,Matsunaga, Toshiyuki,Ikari, Akira
-
p. 10396 - 10411
(2020/11/02)
-
- Co-sensitization of the HD-2 complex with low-cost cyanoacetanilides for highly efficient DSSCs
-
The photophysical and electrochemical properties of new targeted 2-cyanoacetanilide-based dyes are illustrated. New cyanoacetanilides SA7-10 were synthesized and employed as co-sensitizers in DSSCs. The chemical structures of these 2-cyanoacetanilides differ according to the substituent at the benzene ring (-H,-Me,-OMe and-NEt2), with the anchoring moiety being the same, a-COOH group. Furthermore, a density functional theory (DFT) calculation has shown an effective intermolecular charge transfer character, the HOMOs of SA7-10 are mainly located on the corresponding donor part, and their LUMOs are located on carboxylic acid moieties as the acceptor. Interestingly, using photosensitizers SA7-10 as co-sensitizers with HD-2 dye causes an improvement in their photovoltaic performances. Among the dyes, SA10 co-sensitized with HD-2 displayed an overall efficiency of 8.25%, a JSC of 19.5 mA cm-2, a VOC of 0.65 V and an FF of 64.35 compared to 7.46%, 19 mA cm-2, 0.64 V and 60.54, respectively, of HD-2 only. Moreover, the electrochemical impedance spectroscopy (EIS) data of SA7-10 and HD-2 were found to be in accordance with the obtained photovoltaic parameters. Finally, the results indicated that 2-cyanoacetanilide-based dyes were utilized as promising co-sensitizers due to their easy preparation methods and their relatively small size.
- Elmorsy, Mohamed R.,Lyu, Luping,Su, Rui,Abdel-Latif, Ehab,Badawy, Safa A.,El-Shafei, Ahmed,Fadda, Ahmed A.
-
p. 281 - 288
(2020/03/03)
-
- New pyrazolopyrimidine derivatives with anticancer activity: Design, synthesis, PIM-1 inhibition, molecular docking study and molecular dynamics
-
In this study, new pyrazolopyrimidine derivatives were designed and evaluated for anticancer activity. PIM-1 inhibitiory activity were measured for the most potent compounds. Molecular docking study and molecular dynamics were also done. Thus, the novel derivatives of pyrazolo[1,5-a]pyrimidine have been synthesized and characterized using different spectroscopic techniques. HMBC and NOESY experiments were used to confirm regiospecific structure of pyrimidine ring. The newly synthesized derivatives were evaluated for their antitumor activities against HCT-116 and MCF-7 cell lines. These derivatives showed clear in vitro antitumor activities. Compound 5h showed the highest bioactivity (IC50 = 1.51 μM) against HCT-116 cell line. While, compound 6c was the most potent derivative, its IC50 was 7.68 μM against MCF-7 cell line. Compounds 5c, 5g, 5h, 6a and 6c showed PIM-1 inhibitory activity with IC50 of 1.26, 0.95, 0.60, 1.82, 0.67, respectively μM that could be correlated with their cytotoxic effect. Molecular docking study was done to predict the mode of binding of the target compounds inside PIM-1 active site. The molecular dynamic simulation was conducted in order to evaluate stability of binding of the tested compounds.
- Hassan, Marwa H. A.,Kamel, Gehan,Khedr, Mohammed A.,Lamie, Phoebe F.,Philoppes, John N.
-
-
- Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists
-
The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated β-arrestin recruitment signaling (IC50 = 1.1±0.01 μM) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment.
- Chen, Wenmin,Neamati, Nouri,Xue, Ding
-
-
- Synthesis, anti-varicella-zoster virus and anti-cytomegalovirus activity of 4,5-disubstituted 1,2,3-(1H)-triazoles
-
Background: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug resistance. The development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action is greatly required. Objective: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs. Methods: A series of novel 5-(benzylamino)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were evaluated in vitro. Results: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK? VZV strains. Conclusion: 5-(Benzylamino)-1H-1, 2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs.
- Yuan, Wei-Yuan,Chen, Xue,Liu, Ning-Ning,Wen, Yi-Ning,Yang, Bei,Andrei, Graciela,Snoeck, Robert,Xiang, Yu-Hong,Wu, Yong-Wei,Jiang, Zhen,Schols, Dominique,Zhang, Zhuo-Yong,Wu, Qin-Pei
-
p. 801 - 812
(2019/11/02)
-
- Synthesis, characterization, and docking studies of novel cyanopyridone analogs with serotonin 5-HT1B receptor agonists
-
The medications in use for treating migraine are directed either towards inhibiting the characteristic migraine pain or towards preventing it from occurring. In this pursuit, ergotamine and sumatriptan class of 5-HT1B receptor agonists have been proved to be extremely effective. Further research into this field led us to design cyanopyridone derivatives that were synthesized through cyclization of 2-cyano-N-phenylacetamides with malonitrile and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. The synthesized cyanopyridones analogs, when docked with active site of 5-HT1B receptor, showed better binding affinity compared to standard antimigraine medications. Additionally, in silico ADME prediction for drug-likeness and pharmacokinetics revealed that all compounds are safer and can be used as antimigraine medicine. The structure of the synthesized compounds has been elucidated on the basis of spectral analysis.
- Baitha, Amresh,Upadhyay, Manish,Gopinathan, Ajay,Krishnan, Karthik,Dabholkar, Vijay V.
-
supporting information
p. 844 - 851
(2019/03/26)
-
- 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
-
Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
- Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
-
supporting information
p. 179 - 192
(2019/01/04)
-
- Identification of some novel pyrazolo[1,5-a]pyrimidine derivatives as InhA inhibitors through pharmacophore-based virtual screening and molecular docking
-
The InhA inhibitors play key role in mycolic acid synthesis by preventing the fatty acid biosynthesis pathway. In this present article, Pharmacophore modelling and molecular docking study followed by in silico virtual screening could be considered as effective strategy to identify newer enoyl-ACP reductase inhibitors. Pyrrolidine carboxamide derivatives were opted to generate pharmacophore models using HypoGen algorithm in Discovery studio 2.1. Further it was employed to screen Zinc and Minimaybridge databases to identify and design newer potent hit molecules. The retrieved newer hits were further evaluated for their drug likeliness and docked against enoyl acyl carrier protein reductase. Here, novel pyrazolo[1,5-a]pyrimidine analogues were designed and synthesized with good yields. Structural elucidation of synthesized final molecules was perform through IR, MASS, 1H-NMR, 13C-NMR spectroscopy and further tested for its in vitro anti-tubercular activity against H37Rv strain using Microplate Alamar blue assay (MABA) method. Most of the synthesized compounds displayed strong anti-tubercular activities. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study.
- Modi, Palmi,Patel, Shivani,Chhabria, Mahesh T.
-
p. 1736 - 1749
(2018/05/14)
-
- Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides
-
The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 μM).
- Demjén, András,Alf?ldi, Róbert,Angyal, Anikó,Gyuris, Márió,Hackler, László,Szebeni, Gábor J.,W?lfling, János,Puskás, László G.,Kanizsai, Iván
-
-
- Development of the First Two-Pore Domain Potassium Channel TWIK-Related K+ Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity
-
The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.
- Vivier, Delphine,Soussia, Ismail Ben,Rodrigues, Nuno,Lolignier, Stéphane,Devilliers, Ma?ly,Chatelain, Franck C.,Prival, Laetitia,Chapuy, Eric,Bourdier, Geoffrey,Bennis, Khalil,Lesage, Florian,Eschalier, Alain,Busserolles, Jér?me,Ducki, Sylvie
-
p. 1076 - 1088
(2017/02/19)
-
- Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
-
With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18–1.2 μM) at no toxic concentrations (CC50 > 250 μM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents.
- Desantis, Jenny,Nannetti, Giulio,Massari, Serena,Barreca, Maria Letizia,Manfroni, Giuseppe,Cecchetti, Violetta,Palù, Giorgio,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
-
p. 128 - 139
(2017/07/03)
-
- Hypervalent Iodine(III)-Promoted Phenyl Transfer Reaction from Phenyl Hydrazides to Nitriles
-
A useful transformation of nitriles to N-phenyl amides has been achieved through a novel intermolecular phenyl transfer reaction from phenyl hydrazides and N-addition to nitriles in the presence of PIFA under mild and solvent-free conditions. This cross-coupling reaction includes the oxidative cleavage of sp2 C-N bonds of phenyl hydrazides to form a phenyl radical and the subsequent N-addition to cyanos to form new sp2 C-N bonds and provides efficient access to various N-phenyl amides in moderate to good yields under mild reaction conditions.
- Yan, Yan,Zhang, Zhiguo,Wan, Yameng,Zhang, Guisheng,Ma, Nana,Liu, Qingfeng
-
supporting information
p. 7957 - 7963
(2017/08/14)
-
- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
-
Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
-
p. 7487 - 7499
(2015/07/15)
-
- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
-
Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
-
p. 7487 - 7499
(2015/11/27)
-
- Microwave-promoted direct amidation of unactivated esters catalyzed by heteropolyanion-based ionic liquids under solvent-free conditions
-
Abstract A simple and efficient procedure for the synthesis of amides directly from unactivated esters and amines catalyzed by heteropolyanion-based ionic liquids under microwave-promoted and solvent-free conditions has been reported. The practical protocol was found to be compatible with different structurally diverse substrates. Moderate to excellent yields, solvent-free media, and operational simplicity are the main highlights. Furthermore, the heteropolyanion-based ionic liquids were easily reusable for this amidation.
- Fu, Renzhong,Yang, Yang,Ma, Yunsheng,Yang, Fei,Li, Jingjing,Chai, Wen,Wang, Quan,Yuan, Rongxin
-
supporting information
p. 4527 - 4531
(2015/06/30)
-
- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
-
Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
-
supporting information
p. 7590 - 7599
(2014/12/11)
-
- One pot synthesis of novel cyanopyridones as an intermediate of bioactive pyrido[2,3-d]pyrimidines
-
Synthesis, structural characterization, and biological activity studies of novel pyrido[2,3-d]pyrimidines (10a-h, 11a-h) are described. Cyclization of cynoacetamides (4, 5) with malonitrile (7) and aldehyde (6a-h) via Hantzsch pyridine synthesis afforded cyanopyridones (8a-h, 9a-h), which on cyclization with formic acid under microwave conditions led to the final product. All the reactions are significantly faster and the isolated yields are remarkably higher in microwave conditions compared to the conventionally heated reactions. The compounds were tested in vitro for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtillus, Staphylococcus aureus, and Micrococcus luteus and antifungal activity against Trichphyton longifusus, Candida albicans, Microsporum canis, Fusarium solani. Compounds 10b, 10e, 11b and 11e exhibited good antibacterial and antifungal activities compared with standards.
- Khatri, Taslimahemad T.,Shah, Viresh H.
-
p. 366 - 376
(2014/08/18)
-
- A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines
-
A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently synthesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)acrylamides and selected β-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a β-keto ester to 2-cyano-3,3-bis(methylthio) acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3- (methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine.
- Kumar, Sukeerthi,Thakur, Rajni R.,Margal, Sanjay R.,Thomas, Abraham
-
supporting information
p. 5112 - 5118
(2013/06/27)
-
- An efficient synthesis of 2-aminothiophenes via the gewald reaction catalyzed by an N-methylpiperazine-functionalized polyacrylonitrile fiber
-
A new N-methylpiperazine-functionalized polyacrylonitrile fiber has been developed to catalyze the Gewald reaction between 2,5-dihydroxy-1,4-dithiane and activated nitriles to afford 3-substituted 2-aminothiophenes in good to excellent yields (65-91%). Low catalyst loading (8.0 mol%), simple procedure, high yields, excellent recyclability, and reusability (up to 10 times with minimal loss of catalytic activity) are attractive features of this fiber catalyst. Georg Thieme Verlag Stuttgart · New York.
- Ma, Lichao,Yuan, Liwei,Xu, Changzhu,Li, Guowei,Tao, Minli,Zhang, Wenqin
-
supporting information
p. 45 - 52
(2013/03/13)
-
- Synthesis of some novel thieno[3,2-d]pyrimidines as potential cytotoxic small molecules against breast cancer
-
A variety of novel thieno[3,2-d]pyrimidines with different decorating functional groups were synthesized as a part of a study aiming to enrich the arsenal of chemotherapeutic agents for the treatment of cancer. The design of synthetic molecules based on DNA-interchelating properties by hydrogen bond formation. The reported compounds herein are: 4-aminothienopyrimidine derivatives 4a, b and their 4-substituted phenylamino analogues 8a, b; 4-thienopyrimidin-4-ones 5a, b; N-alkyl thienopyrimidin-4-ones 6a-g; 4-chlorothienopyrimidines 7a, b and thienopyrimidoquinazolinones 9a, b which are the structural mimics of 8a, b. The synthesized molecules were evaluated for their in vitro cytotoxic activity against human breast cancer cell line (MCF-7). Biological screening revealed varying cytotoxic potencies of the tested molecules compared with Doxorubicin as a reference drug. The cytotoxicity results from the study suggested that the synthesized molecules are potential antitumor agents and compound 4a was the most potent with an IC50 2.04 nM.
- Kandeel, Manal,Abdelhameid, Mohammed Kamal,Eman, Kamal,Labib, Madlen Berty
-
p. 637 - 647
(2013/07/27)
-
- Designing, synthesis, and characterization of some novel coumarin derivatives as probable anticancer drugs
-
Coumarin is a naturally occurring oxygen heterocyclic having multifarious medicinal properties, hence used as a lead compound for designing new potent analogs. Based on the X-ray crystal structure of complexes of inhibitors containing coumarin nucleus with human NAD(P)H:quinone oxidoreductase-1 and human phosphodiesterase 4B enzymes, some novel coumarin derivatives have been designed as probable inhibitors specifically for pancreatic cancer. These two enzymes are overexpressed in various tumors, the former specifically in pancreatic cancer. The computational analysis by e-pharmacophore and docking studies suggested that specific groups at position 8 of 4-methyl-7- hydroxycoumarin have anticancer activity against skin cancer in mice and can enhance the anti-tumor activity. The chemical syntheses of 4-methyl-7- hydroxycoumarin and its 8-formyl derivative were carried out using Pechmann's condensation followed by Duffs reaction. Treatment of the 8-formyl derivative with nine different N,N-di substituted cyanoacetamides in the presence of piperidine afforded the corresponding nine new 8-substituted-4-methyl-7- hydroxycoumarin derivatives. These compounds were characterized by IR, 1H, 13C NMR, mass spectra and elemental analysis. Intriguingly, molecular docking suggested a remarkable binding pose for all the nine coumarin derivatives vis-a-vis coumarin itself, opening further options for designing inhibitors for tumor suppression. From the docking simulation study, it was concluded that the derived coumarin derivatives are active against more than one proteins and most importantly addition of substituents at the 8th position of 4-methyl-7-hydroxycoumarin support the possibility of new coumarin derivatives having comparatively higher binding affinity and therefore more potent inhibitors.
- Manidhar, Darla Mark,Kesharwani, Rajesh Kumar,Reddy, N. Bakthavatchala,Reddy, C. Suresh,Misra, Krishna
-
p. 4146 - 4157
(2013/09/02)
-
- 4-phenyl-α-cyanocinnamic acid amide: Screening for a negative ion matrix for MALDI-MS imaging of multiple lipid classes
-
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has become a method of choice in lipid analysis, as it provides localization information for defined lipids that is not readily accessible with nonmass spectrometric methods. Most current MALDI matrices have been found empirically. Nevertheless, preferential matrix properties for many analyte classes are poorly understood and may differ between lipid classes. We used rational matrix design and semiautomated screening for the discovery of new matrices suitable for MALDI-IMS of lipids. Utilizing Smartbeam- and nitrogen lasers for MALDI, we systematically compared doubly substituted α-cyanocinnamic acid derivatives (R1-CCA-R2) with respect to their ability to serve as negative ion matrix for various brain lipids. We identified 4-phenyl-α-cyanocinnamic acid amide (Ph-CCA-NH 2) as a novel negative ion matrix that enables analysis and imaging of various lipid classes by MALDI-MS. We demonstrate that Ph-CCA-NH2 displays superior sensitivity and reproducibility compared to matrices commonly employed for lipids. A relatively small number of background peaks and good matrix suppression effect could make Ph-CCA-NH2 a widely applicable tool for lipid analysis.
- Fueloep, Annabelle,Porada, Martina B.,Marsching, Christian,Blott, Henning,Meyer, Bjoern,Tambe, Suparna,Sandhoff, Roger,Junker, Hans-Dieter,Hopf, Carsten
-
p. 9156 - 9163
(2013/10/21)
-
- SMALL MOLECULES AS EPIGENETIC MODULATORS OF LYSINE-SPECIFIC DEMETHYLASE 1 AND METHODS OF TREATING DISORDERS
-
The invention provides for novel compounds which are inhibitors of lysine- specific demethylase 1 (LSDl). Such compounds may be used to treat disorders, including cancer.
- -
-
Page/Page column 42; 43
(2012/03/27)
-
- Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1
-
The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.
- Hazeldine, Stuart,Pachaiyappan, Boobalan,Steinbergs, Nora,Nowotarski, Shannon,Hanson, Allison S.,Casero, Robert A.,Woster, Patrick M.
-
p. 7378 - 7391
(2012/10/29)
-
- Synthesis of some substituted isoxazolo [5,4-d] pyrimidine-4(5H)-ones and their biological evaluation
-
Substituted anilines vk'ere condensed Wiih ethyl cyanoacetate in xylene to get corresponding 2-cyano-N-phenylacetamides 1a-1h, which upon reaction with sodium bicarbonate and acetic anhydride gave corresponding compounds 2-cyano-3-hydroxy-N-phenylbut-2-enamides 2a-2h, which further upon reaction with hydroxyl amine hydrochloride in methanol yielded corresponding 5-amino-3-methyl-N-phenylisoxazole-4-carboxamides 3a-3h. 3a-3h when treated with acetic anhydride and triethyl orthoformate, gave substituted isoxazolo [5,4-d] pyrimidin-4 (5H)-ones 4a-4h.
- Godhani,Kaila,Sanghani,Dobariya
-
p. 225 - 228
(2013/09/24)
-
- Synthesis and insecticidal activities of novel neonicotinoid analogs bearing an amide moiety
-
Figure represented. A series of novel neonicotinoid analogs containing an amide moiety were synthesized, characterized, and subsequently evaluated for their insecticidal activity. According to the preliminary bioassay, the compounds 6c, 6e, 6f, 6j, 6n, and 6r exhibited > 50% activity against Nilaparvata lugens at 100 mg/L. Amongst the active compounds, 6f and 6r revealed insecticidal activities similar to that displayed by standard buprofezin. J. Heterocyclic Chem., (2011)
- Wu, Jian,Yang, Song,Song, Bao-An,Bhadury, Pinaki S.,Hu, De-Yu,Zeng, Song,Xie, Hua-Peng
-
scheme or table
p. 901 - 906
(2011/10/02)
-
- Cell-permeable iminocoumarine-based fluorescent dyes for mitochondria
-
A class of small molecule fluorophores, 2-iminocoumarin-3-carboxamide derivatives, has been developed by a rapid microwave-assisted process. These fluorescent probes are cell membrane permeable with low cytotoxicity and able to selectively stain organelles in living cells.
- Guo, Diliang,Chen, Tao,Ye, Deju,Xu, Jinyi,Jiang, Hualiang,Chen, Kaixian,Wang, Hui,Liu, Hong
-
supporting information; experimental part
p. 2884 - 2887
(2011/07/07)
-
- Microwave reaction of diazonium salts with nitrites
-
A series of aryldiazonium tetrafluorborates dissolved in nitrites have been converted into the corresponding anilides in almost quantitative yield in 1 min by microwave irradiation. When bromoacetonitrile was used, 2,4-bis(bromophenyl) -quinazoline was formed. The reaction of malononitrile with the diazonium salt, in DMF as a solvent, afforded 2-(dimethylaminomethylene) malononitrile and phenylhydrazone propanedinitrile.
- Saez, Rebeca,Dolores Otero,Batanero, Belen,Barba, Fructuoso
-
body text
p. 492 - 494
(2009/04/06)
-
- Enols of substituted cyanomalonamides
-
(Chemical Equation Presented) Twenty open-chain mono-, di-, and trialkyl and aryl-N-substituted cyanomalonamides R2R1NCOCH-(CN) CONHR3 were prepared. In solution, signals for both amide and a single enol are mostly observed, despite the potential for E and Z isomeric enols. The equilibrium (KEnol) values between the amides and the enols were determined in different solvents by NMR spectra. They decrease on increasing the polarity of the solvent in the order CDCl3 ~ C6D6 > THF-d8 (CD3)2CO > CD3CN > DMF-d7 > DMSO-d6. For the R1R2NCOCH(CN)CONHR3 system when R1 = R2 = H, Me or R1 = H, R2 = Me, K Enol for R3 follows the order: C6F5 > Ph ≥ An ≥ i-Pr ≥ t-Bu, and for R1, R2:H, H > Me, H > Me, Me in all solvents. A unique feature is the appreciable % enol in DMSO-d6 when R1 = R2 = H, in contrast with enol systems with other electron-withdrawing groups (EWGs). Calculations (B3LYP/6-31G**) corroborate the higher KEnol values for less alkyl-substituted systems, showing that in the most stable conformer when R1 = H, R2 = R3 = Me the N-hydrogens are closer to the CN group. The order of promoting substituents for enol of amide formation is CONH2 > CO2CH2CF3 > CO2Me > CONHMe. The solid-state structures of the isolated species, determined by X-ray crystallography, were either amides or enols, and a higher KEnol(CDCl3) value does not ensure a solid enol structure. In no system were both solid species isolated. The X-ray structures of the enols were temperature-dependent. In most cases, the difference between the O-H and O...H bond lengths at low temperature were appreciable, but they become closer at the higher temperature. Similar tendency for either the C=C/C-C or the C-O/C=O bonds was observed. This is ascribed to a hydrogen shift between two regioisomeric enols in an asymmetric double-well potential, which becomes faster at a higher temperature. Calculations show that the enol structures are nonsymmetrical, resembling the lower temperature structures, even when they are chemically symmetrical, but the energy differences between the two regioisomers are 1 kcal. The hydrogen bonds in the enol moiety are strong, with O...O distances 2.45 A, and are resonance-assisted hydrogen bonds. IR spectra in solution and the solid state qualitatively corroborate the NMR and X-ray structure determination.
- Basheer, Ahmad,Yamataka, Hiroshi,Ammal, Salai Cheettu,Rappoport, Zvi
-
p. 5297 - 5312
(2008/02/08)
-
- INDOL-1-YL-ACETIC ACID DERIVATIVES
-
The invention relates to indol-1-yl-acetic acid derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and methods of treatment comprising administration of said compounds.
- -
-
Page/Page column 67
(2010/02/14)
-
- Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries
-
2-Pyridone and 2-quinolone analogues are well-known biologically active heterocyclic scaffolds. Libraries of 3,5,6-substituted 2-pyridone derivatives are generated by rapid microwave assisted solution phase methods using a one-pot, two-step protocol. The three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal and methylene active nitriles, leads to 2-pyridones and fused analogues in moderate to good overall yields and high purities. The proposed mechanism of this novel multi-component reaction, structure elucidation of products and intermediates are discussed.
- Gorobets, Nikolay Yu.,Yousefi, Behrooz H.,Belaj, Ferdinand,Kappe, C. Oliver
-
p. 8633 - 8644
(2007/10/03)
-
- Modulators of LXR
-
Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of nuclear receptors, including liver X receptor (LXR) and orphan nuclear receptors. In certain embodiments, the compounds are N-substituted pyridones.
- -
-
-
- α-Cyanocinnamide derivatives: A new family of non-peptide, non-sulfhydryl inhibitors of ras farnesylation
-
Farnesylation of Ras and other proteins is required for their membrane attachment and normal function. Here we report on the synthesis of α-cyanocinnamide derivatives, a new family of farnesyltransferase inhibitors. These compounds are nonpeptidic and do not contain sulfhydryl groups. The most potent compound is a pure competitive inhibitor with respect to the Ras protein and mixed competitive with respect to farnesyl diphosphate. Selectivity studies against geranylgeranyltransferase and biological activities of selected compounds are described. Copyright (C) 1999.
- Poradosu, Enrique,Gazit, Aviv,Reuveni, Hadas,Levitzki, Alexander
-
p. 1727 - 1736
(2007/10/03)
-
- 3-hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran2- ylidene)- and 2-cyano-2-(tetrahydropyran-2-ylidene)acetamides: Synthesis, structure, and solvent-dependent (Z)/(E)-isomerism
-
3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2- ylidene)- and 2-cyano-2-(tetrahydropyran-2-ylidene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 1H- NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular O-H O=C bond both in the solid state and in (D6)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,b-8a,b is solvent-dependent. In the solid state and in CDCI3 solution, the compounds adopt an extended conformation of type I or III, while, in (D6)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type II or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(t-Bu) derivatives 7a and 71) having the highest barrier of rotation around the C=C bond. The whole body of experimental evidence together with the results of molecular- mechanics calculations with I-IV, indicate that, in DMSO, two (E)/(Z)- isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates k(I.II) and k(III.IV) in the NMR time-scale might be responsible for the detection of only two isomers.
- Papageorgiou,Akyel,Borer,Oberer,Rihs
-
p. 1319 - 1328
(2007/10/03)
-
- Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl- 3-hydroxy. N-[3'-methyl-4'-(trifluoromethyl)phenyl]propenamide and related compounds
-
The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
- Kuo, Elizabeth A.,Hambleton, Philip T.,Kay, David P.,Evans, Phillip L.,Matharu, Saroop S.,Little, Edward,McDowall, Neil,Jones, C. Beth,Hedgecock, Charles J. R.,Yea, Christopher M.,Chan, A. W. Edith,Hairsine, Peter W.,Ager, Ian R.,Tully, W. Roger,Williamson, Richard A.,Westwood, Robert
-
p. 4608 - 4621
(2007/10/03)
-
- Synthesis and Biological Activity of a Series of Diaryl-Substituted α-Cyano-β-hydroxypropenamides, a New Class of Anthelmintic Agents
-
A series of α-cyano-β-hydroxypropenamides was prepared and tested for anthelmintic activity. α-Cyano-β-hydroxy-N--3-propenamide (1) showed good activity against the nematode Nematospirodes dubius in a mixed parasite infection in mice; several of the analogues were also effective against the cestode Hymenolepis nana.In sheep trials, 1 caused 100percent reduction of the hematophagous nematode Haemonchus contortus after a single dose of 20 mg/kg but did not show satisfactory control of Trichostrongylus colubriformis or Ostertagia circumcincta.Against the liver fluke Fasciola hepatica, 1 suppressed egg production but only temporarily, suggesting that the adult flukes were not eliminated.Mechanism of action studies on 1 using Ascaris mitochondria showed it to be an uncoupler of oxidative phosphorylation.
- Sjogren, Eric B.,Rider, Michael A.,Nelson, Peter H.,Bingham, Stanford,Poulton, Anthony L.,et al.
-
p. 3295 - 3301
(2007/10/02)
-
- Tyrphostins. 2. Heterocyclic and α-Substituted Benzylidenemalonitrile Tyrphostins as Potent Inhibitors of EGF Receptor and ErbB2/neu Tyrosine Kinases
-
We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins.The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalonitrile moiety.In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides.Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2).These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
- Gazit, Aviv,Osherov, Nir,Posner, Israel,Yaish, Pnina,Poradosu, Enrique,et al.
-
p. 1896 - 1907
(2007/10/02)
-
- SYNTHESIS OF 2-AMINO-1-AZIRINES AND THEIR REACTIONS WITH CARBOXYLIC ACIDS
-
A method was developed for the synthesis of 2-amino-1-azirines under the conditions of a modified Neber reaction.Their reactivities with respect to mono- and dicarboxylic acids and thiocarboxylic acids were investigated.
- Eremeev, A. V.,Piskunova, I. P.,El'kinson, R. S.
-
p. 998 - 1002
(2007/10/02)
-
- Alphacarbamoyl-pyrrolpropionitriles
-
1-Substituted-β-oxo-α-phenylcarbamoyl-pyrrolpropionitriles, e.g. those of the formula STR1 their alkylenol ethers or alkanoylenol esters and salts thereof are antiinflammatory and antiarthritic agents.
- -
-
-