103-04-8Relevant articles and documents
The synthesis and characterization of tetramic acid derivatives as Mdm2-p53 inhibitors
Muszak, Damian,?abuzek, Beata,Brela, Mateusz Z.,Twarda-Clapa, Aleksandra,Czub, Miroslawa,Musielak, Bogdan,Surmiak, Ewa,Holak, Tad A.
, p. 161 - 174 (2019)
We present syntheses, prediction of tautomer forms and activities of the second generation of the Mdm2-p53 inhibitors that are based on the tetramic acid scaffold. The inhibitors do not contain 6-chloroindole. Binding of these compounds to Mdm2 was checked by two orthogonal methods: the fluorescence polarization and the 1H-15N HSQC NMR titration experiments. We discovered that the 3-phenylthio-substituted tetramic acid derivatives exist in solution solely in their enol forms which is in contrast to the similar 3-aliphatic substituted derivatives. The inhibitory (Ki) and dissociation (KD) constants are in low micromolar ranges with the best binding compound 9a having KD = 2.9 μM. Furthermore, our data show that the compounds indeed bind to the p53-binding pocket of Mdm2 and do not cause dimerization of Mdm2. The current work provides solid base for further rational design of the Mdm2/p53 inhibitors.
Leishmanicidal activities of novel synthetic furoxan and benzofuroxan derivatives
Dutra, Luiz Ant?nio,De Almeida, Letícia,Passalacqua, Thais G.,Reis, Juliana Santana,Torres, Fabio A. E.,Martinez, Isabel,Peccinini, Rosangela Gon?alves,Chin, Chung Man,Chegaev, Konstantin,Guglielmo, Stefano,Fruttero, Roberta,Graminha, Marcia A. S.,Dos Santos, Jean Leandro
, p. 4837 - 4847 (2014)
A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis. Copyright
3-Thiolated 2-azetidinones: Synthesis and in vitro antibacterial and antifungal activities
Zarei, Maaroof,Mohamadzadeh, Masoud
, p. 5832 - 5840 (2011)
A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.
Novel NO-releasing scopoletin derivatives induce cell death via mitochondrial apoptosis pathway and cell cycle arrest
Chen, Cheng,Chen, Li,Lei, Zhichao,Li, Na,Shi, Zhixian,Sun, Jianbo,Wang, Yujin
, (2020)
A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC50 = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted.
Oxidation of Organic Sulfides by Permanganate Ion
Lee, Donald G.,Chen, Tao
, p. 5346 - 5348 (1991)
The current literature on the oxidation of sulfides by permanganate contains a suggestion that the reaction mechanism involves an electrophilic oxygen transfer in an SN2-like mechanism.Contrary to this assumption, it is argued that the experimental facts obtained from a study of the oxidation of (arylthio)acetic acids can more reasonably be accommodated in a mechanism that is initiated by the formation of a coordinate covalent bond utilizing an unshared pair of sulfur electrons and empty manganese d-orbitals.Rearrangement of this intermediate then leads to the formation of sulfoxide and manganate(V) ion.
Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis
Fernandes, Guilherme Felipe dos Santos,de Souza, Paula Carolina,Marino, Leonardo Biancolino,Chegaev, Konstantin,Guglielmo, Stefano,Lazzarato, Loretta,Fruttero, Roberta,Chung, Man Chin,Pavan, Fernando Rogério,dos Santos, Jean Leandro
, p. 523 - 531 (2016)
Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in?vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90values ranging from 1.03 to 62?μM (H37Rv) and 7.0–50.0?μM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5?cells) and 1.25–34.78 (J774A.1?cells). In addition, it was characterized for those compounds logPo/wvalues between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.
KINETICS AND MECHANISM OF OXIDATION OF (ARYLTHIO)ACETIC ACIDS BY PYRIDINIUM HYDROBROMIDE PERBROMIDE
Karunakaran, K.,Elango, K. P.
, p. 429 - 434 (1995)
Oxidation of several monosubstituted (phenylthio)acetic acids (PTAA) by pyridinium hydrobromide perbromide (PHPB) was studied in aqueous acetic acid.The reaction is first order with respect to PHPB.Michaelis-Menten type kinetics are observed with respect to (arylthio)acetic acid.The effect of solvent composition indicates that the transition state is more polar than the reactants.The formation constants of the intermediate substrate-PHPB complexes and the rates of their decomposition were determined at different temperatures.The rates of oxidation of para and meta-substituted (phenylthio)acetic acids were correlated with Hammett's substituent constants.The ρ value is -1.60 at 35 deg c.The rates of oxidation of ortho substituted compounds are correlated with Charton's triparametric equation.A mechanism involving the decomposition of the intermediate complex in the slow rate-determining step affording a sulphonium ion which hydrolyses in a subsequent fast step to the sulphoxide is proposed.
Hybrids of phenylsulfonylfuroxan and coumarin as potent antitumor agents
Liu, Ming-Ming,Chen, Xiao-Yu,Huang, Yao-Qing,Feng, Pan,Guo, Ya-Lan,Yang, Gong,Chen, Ying
, p. 9343 - 9356 (2014)
Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.
Identification of New Nitric Oxide-Donating Peptides with Dual Biofilm Eradication and Antibacterial Activities for Intervention of Device-Related Infections
Fei, Yue,Wu, Jianbing,An, Hong-Wei,Zhu, Kai,Peng, Bo,Cai, Junquan,Zhang, Yihua,Li, Li-Li,Wang, Hao,Huang, Zhangjian
, p. 9127 - 9135 (2020)
Implantable medical device-related infections with biofilms have become a significant challenge in clinics. Based on the potential bacteria biofilm dispersing effect of nitric oxide (NO) and the unique antibacterial activity of antimicrobial peptides (AMP), we synthesized five peptides and selected the most potent one to conjugate its N-terminal with a furoxan moiety to offer a hitherto unknown NO-donating antimicrobial peptide (FOTyr-AMP), which exhibited Staphylococcus aureus and Escherichia coli biofilm dispersion and eradication, and potent antibacterial activities in vitro. In an implanted biofilm infection mice model, topical subcutaneous injection of FOTyr-AMP allowed synergetic eradication of bacterial biofilms and potent antibacterial activity, superior to the antibiotic cephalosporin C. Given the low hemolysis effect, little influence on the blood pressure, and potent in vivo efficacy of FOTyr-AMP, it is clear that subcutaneous administration of FOTyr-AMP could be a promising approach for the intervention of medical device-related biofilm infections with desirable safety.
-
Field,L.,Carlile,C.G.
, p. 3170 - 3176 (1961)
-
PhSH - (catalytic) KF as an efficient protocol for chemoselective ester O-alkyl cleavage under non-hydrolytic neutral condition
Nayak, Mrinal K.,Chakraborti, Asit K.
, p. 297 - 298 (1998)
Methyl esters are chemoselectively deprotected by thiophenol in presence of catalytic amount of KF in dry NMP (1-Methyl-2-pyrrolidinone) under non-hydrolytic neutral condition.
Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine
Zhao, Nan,Tian, Kang-Tao,Cheng, Ke-Guang,Han, Tong,Hu, Xu,Li, Da-Hong,Li, Zhan-Lin,Hua, Hui-Ming
, p. 2971 - 2978 (2016)
The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a-c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.
Chromone 3-piperazine linked furazan derivative as well as preparation method and application thereof
-
Paragraph 0014; 0021; 0024, (2021/05/05)
The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 3-piperazine linked furazan derivatives with antitumor activity and a new application of the chromone 3-piperazine linked furazan derivatives in preparation of antitumor medicines. The chromone 3-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof disclosed by the invention are as shown in a general formula I in the specification. Wherein R is described in the claims and the specification.
Chromone 2-piperazine linked furazan derivative as well as preparation method and application thereof
-
Paragraph 0014; 0021; 0024, (2021/05/05)
The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 2-piperazine linked furazan derivatives with antitumor activity and a new application of the chromone 2-piperazine linked furazan derivatives in preparation of antitumor medicines. The chromone 2-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof disclosed by the invention are as shown in a general formula I in the specification. Wherein R is described in the claims and the specification.
