- KMnO4-catalyzed chemoselective deprotection of acetate and controllable deacetylation-oxidation in one pot
-
A novel and efficient protocol for chemoselective deacetylation under ambient conditions was developed using catalytic KMnO4. The stoichiometric use of KMnO4 highlighted the dual role of a heterogeneous oxidant enabling direct access to aromatic aldehydes in one-pot sequential deacetylation-oxidation. The reaction employed an alternative solvent system and allowed the clean transformation of benzyl acetate to sensitive aldehyde in a single step while preventing over-oxidation to acids. Use of inexpensive and readily accessible KMnO4 as an environmentally benign reagent and the ease of the reaction operation were particularly attractive, and enabled the controlled oxidation and facile cleavage of acetate in a preceding step. This journal is
- Gurawa, Aakanksha,Kumar, Manoj,Rao, Dodla S.,Kashyap, Sudhir
-
supporting information
p. 16702 - 16707
(2020/10/27)
-
- Synthesis of cinnamic acid derivatives and leishmanicidal activity against Leishmania braziliensis
-
Leishmania braziliensis is one of the pathogenic agents of cutaneous and mucocutanoeous leishmaniasis. There are no validated vaccines to prevent the infection and the treatment relies on drugs that often present severe side effects, which justify the efforts to find new potential antileishmanial drugs. An alternative to promote the discovery of new drugs would be the association of different chemical groups of bioactive compounds. Here we describe the synthesis and bioactivity evaluation against L. braziliensis of cinnamic acid derivatives possessing isobenzofuranone and 1,2,3-triazole functionalities. We tested 25 compounds at 10 μM concentration against extracellular promastigotes and intracellular amastigotes during macrophage infection. Most compounds were more active against amastigotes than to promastigotes. The derivatives (E)-3-oxo-1,3-dihydroisobenzofuran-5-yl-(3,4,5-trimethoxy) cinnamate (5c), (1-(3,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl cinnamate (9g), and (1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl cinnamate (9l) were the most effective presenting over 80% toxicity on L. braziliensis amastigotes. While compound 5c is a cinnamate with an isobenzofuranone portion, 9g and 9l are triazolic cinnamic acid derivatives. The action of these compounds was comparable to amphotericin B used as positive control. Ultrastructural analysis revealed that 5c-treated parasites showed impaired cytokinesis and apoptosis triggering. Taken together, these results highlight the potential of cinnamic acid derivatives in development of novel anti-leishmanial drugs.
- Rodrigues, Michelle Peixoto,Tomaz, Deborah Campos,?ngelo de Souza, Luciana,Onofre, Thiago Souza,Aquiles de Menezes, Wemerson,Almeida-Silva, Juliana,Suarez-Fontes, Ana Márcia,Rogéria de Almeida, Márcia,Manoel da Silva, Adalberto,Bressan, Gustavo Costa,Vannier-Santos, Marcos André,Rangel Fietto, Juliana Lopes,Teixeira, Róbson Ricardo
-
-
- Synthesis of nerol derivatives containing a 1,2,3-triazole moiety and evaluation of their activities against cancer cell lines
-
In the present investigation, a collection of twenty two nerol derivatives, containing 1,2,3-triazolic appendages, was synthesized and screened in vitro for their cytotoxic activity against HL60, Nalm6, and Jurkat human leukemia cells as well as against B16F10 (melanoma cell line). In most cases, derivatives were able to reduce cell viability. The most potent compound (Z)-4-(((3,7-dimethylocta-2,6-dien-1-yl)oxy)methyl)-1-(4-(trifluoromethoxy)benzyl)-1H-1,2,3 triazole showed antiproliferative activity against Jurkat cells and reduced B16F10 cell migration. Physicochemical properties of the compounds were calculated in order to evaluate their potential for drug development. Most of the evaluated physicochemical parameters seemed to be favorable for drug development. In addition, for a better understanding of the biological activity results, 3D quantitative structure-activity relationship (QSAR) studies were carried out. 3D-QSAR studies indicate that the anticancer activities observed for the cell lines HL60 and Jurkat may occur by a similar mechanism of action and the same was found for the Nalm6 and B16F10 cell lines.
- Teixeira, Róbson R.,Da Silva, Adalberto M.,Siqueira, Raoni P.,Gon?alves, Victor Hugo S.,Pereira, Higor S.,Ferreira, Rafaela S.,Costa, Adilson V.,de Melo, Eduardo B.,Paula, Fávero R.,Ferreira, Márcia M.C.,Bressan, Gustavo C.
-
p. 541 - 561
(2019/08/26)
-
- Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates
-
A method for aliphatic fluoride functionalization with a variety of nucleophiles has been reported. Carbon–fluoride bond cleavage is thermodynamically driven by the use of silylated pseudohalides TMS-OMs or TMS-NTf2, resulting in the formation of TMS-F and a trapped aliphatic pseudohalide intermediate. The rate of fluoride/pseudohalide exchange and the stability of this intermediate are such that little rearrangement is observed for terminal fluoride positions in linear aliphatic fluorides. The ability to convert organofluoride positions into pseudohalide groups allows facile nucleophilic attack by a wide range of nucleophiles. The late introduction of the nucleophiles also allows for a wide range of functional-group tolerance in the coupling partners. Selective alkyl fluoride mesylation is observed in the presence of other alkyl halides, allowing for orthogonal synthetic strategies.
- Jaiswal, Amit K.,Prasad, Pragati K.,Young, Rowan D.
-
p. 6290 - 6294
(2019/04/26)
-
- Synthesis and leishmanicidal activity of eugenol derivatives bearing 1,2,3-triazole functionalities
-
In this paper, it is described the synthesis and the evaluation of the leishmanicidal activity of twenty-six eugenol derivatives bearing 1,2,3-triazole functionalities. The evaluation of the compounds on promastigotes of Leishmania amazonensis (WHOM/BR/75/Josefa) showed that eugenol derivatives present leishmanicidal activities with varying degrees of effectiveness. The most active compound, namely 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) (IC50 = 7.4 ± 0.8 μmol L?1), also targeted Leishmania parasites inside peritoneal macrophages (IC50 = 1.6 μmol L?1) without interfering with cell viability. The cytotoxicity of 7k against macrophage cells presented IC50 of 211.9 μmol L?1 and the selective index was equal to 132.5. Under similar conditions, compound 7k was more effective than glucantime and pentamidine, two drugs currently in the clinic. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that eugenol bearing 1,2,3-triazole functionalities may represent a scaffold to be explored toward the development of new agents to treat leishmaniasis.
- Teixeira, Róbson Ricardo,Gazolla, Poliana Aparecida Rodrigues,da Silva, Adalberto Manoel,Borsodi, Maria Paula Gon?alves,Bergmann, Bartira Rossi,Ferreira, Rafaela Salgado,Vaz, Boniek Gontijo,Vasconcelos, Géssica Adriana,Lima, Wallace Pacienza
-
p. 274 - 286
(2018/02/10)
-
- Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
-
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
- Cao, Jiangying,Ma, Chunhua,Zang, Jie,Gao, Shuai,Gao, Qianwen,Kong, Xiujie,Yan, Yugang,Liang, Xuewu,Ding, Qin'ge,Zhao, Chunlong,Wang, Binghe,Xu, Wenfang,Zhang, Yingjie
-
p. 3145 - 3157
(2018/06/01)
-
- Efficient Synthesis of Sulfinate Esters and Sulfinamides via Activated Esters of p -Toluenesulfinic Acid
-
Sulfinate esters were prepared by the process of activating p -toluenesulfinic acid with either cyanuric chloride, methanesulfonyl chloride, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl). Activation of p -toluenesulfinic acid with cyanuric chloride led to the formation of sulfinate esters that were accompanied by the formation of the corresponding sulfones. The use of methanesulfonyl chloride for activation via methanesulfonic p -toluenesulfinic anhydride afforded mixtures of sulfinate esters and methanesulfonates. The use of the carbodiimide EDC proved to yield the best results with the highly selective formation of the target sulfinate esters. The use of trimethylacetic p -toluenesulfinic anhydride or cyanuric chloride to achieve the synthesis of sulfinamides proved to be ineffective due to poor chemoselectivity of the nucleophilic attack on the activated p -toluenesulfinic acid anhydride. Ultimately, the use of EDC-HCl to form the sulfinamides proved to be the best pathway for synthesis.
- Gafur, Sayed Habibul,Waggoner, Stephanie L.,Jacobsen, Eric,Hamaker, Christopher G.,Hitchcock, Shawn R.
-
p. 4855 - 4866
(2018/12/13)
-
- DRUG-LINKER CONJUGATE PHARMACEUTICAL COMPOSITIONS
-
Compositions are disclosed having a cytotoxic and/or vascular disrupting agent (VDA) payload attached to a linker. The linker can be a cathepsin B protease cleavable linker or a non-cleavable linker that may degrade intracellularly. Methods for making and using the compositions are also provided. The compositions can be provided to a patient in need thereof with the composition coming into contact with a cancer cell to activate or release the cytotoxic and/or vascular disrupting agent payload.
- -
-
Paragraph 000222-000224
(2017/05/02)
-
- Inhibition of hypoxia-induced gene transcription by substituted pyrazolyl oxadiazoles: Initial lead generation and structure-activity relationships
-
The transcription factors hypoxia-inducible factor-1 and -2 (HIF-1 and HIF-2) orchestrate a multitude of processes that allow tumor cells to survive under conditions of low oxygen and nutrients, and that lead to resistance to some apoptotic pathways and facilitate invasion and metastasis. Therefore, inhibition of transactivation by HIF has become an attractive target in cancer research. Herein we present the results of a cell-based screening approach that led to the discovery of substituted 1H-pyrazole-3-carboxamides. Chemical optimization of the hit class with respect to potency and metabolic stability is described; it resulted in novel 5-(1H-pyrazol-3-yl)-1,2,4-oxadiazoles that inhibit the hypoxia-induced accumulation of HIF-1α and HIF-2α. The HIF inhibitory potency in the screening cell system was improved from IC 50 190 to 0.7 nM, and significant parts of the SAR are disclosed. For a key compound, the ability to suppress the hypoxia-induced expression of HIF target genes was studied in A549 human lung adenocarcinoma cells. The same compound shows a favorable pharmacokinetic profile in rats after i.v. and p.o. administration. Suppressing HIF target genes: Substituted 5-(1H-pyrazol-3-yl)-1, 2,4-oxadiazoles are presented as a novel chemotype to specifically inhibit the hypoxia-induced transcription of target genes of the transcription factor hypoxia-inducible factor (HIF). The new chemotype was derived from 1H-pyrazole-3-carboxamides that had been discovered from a cell-based screen. We present the optimization of the potency and metabolic stability of the initial screening hit. Copyright
- Haerter, Michael,Thierauch, Karl-Heinz,Boyer, Stephen,Bhargava, Ajay,Ellinghaus, Peter,Beck, Hartmut,Greschat-Schade, Susanne,Hess-Stumpp, Holger,Unterschemmann, Kerstin
-
supporting information
p. 61 - 66
(2014/01/17)
-
- Amine Substituted Methanesulfonamide Derivatives as Vanilloid Receptor Ligands
-
The invention relates to amine substituted methanesulfonamide derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Paragraph 0482; 0492; 0493
(2013/04/10)
-
- SUBSTITUTED PYRAZOLYL-BASED CARBOXAMIDE AND UREA DERIVATIVES BEARING A PHENYL MOIETY SUBSTITUTED WITH AN N-CONTAINING GROUP AS VANILLOID RECEPTOR LIGANDS
-
The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives of formula (R) bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Page/Page column 72
(2013/05/23)
-
- Aryl or N-heteroaryl Substituted Methanesulfonamide Derivatives as Vanilloid Receptor Ligands
-
The invention relates to aryl or N-heteroaryl substituted methanesulfonamide derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Paragraph 0406; 0407
(2013/04/10)
-
- ARYL OR N-HETEROARYL SUBSTITUTED METHANESULFONAMIDE DERIVATIVES AS VANILLOID RECEPTOR LIGANDS
-
The invention relates to aryl or N-heteroaryl substituted methanesulfonamide derivatives of Formula (I) as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Page/Page column 41; 69
(2013/04/13)
-
- AMINE SUBSTITUTED METHANESULFONAMIDE DERIVATIVES AS VANILLOID RECEPTOR LIGANDS
-
The invention relates to amine substituted methanesulfonamide derivatives of formula (I) as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
- -
-
Page/Page column 53
(2013/04/13)
-
- Bio-orthogonal affinity purification of direct kinase substrates
-
Protein phosphorylation is a major mechanism of post-translational protein modification used to control cellular signaling. A challenge in phosphoproteomics is to identify the direct substrates of each protein kinase. Herein, we describe a chemical strate
- Allen, Jasmina J.,Lazerwith, Scott E.,Shokat, Kevan M.
-
p. 5288 - 5289
(2007/10/03)
-
- Tricyclic indole-2-carboxylic acids: Highly in vivo active and selective antagonists for the glycine binding site of the NMDA receptor
-
A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(-)-4 was confirmed by X-ray crystallographic analysis. In particular, 3g (SM-31900) was found to be a highly active glycine antagonist for both in vitro and in vivo assays (Ki = 1.0 ± 0.1 nM, ED50 = 2.3 mg/kg, iv) and also showed high selectivity for the glycine site. In addition, 3g was soluble enough in aqueous media (> 10 mg/mL at pH 7.4) to use for medications by intravenous injection.
- Katayama, Seiji,Ae, Nobuyuki,Kodo, Toru,Masumoto, Shuji,Hourai, Shinji,Tamamura, Chika,Tanaka, Hiroyasu,Nagata, Ryu
-
p. 691 - 701
(2007/10/03)
-
- Changes of Selectivity in the Reactions of Substituted 4-Nitrobenzyl Sulfonates with Nucleophilic Reagents
-
The selectivities for anionic nucleophilic reagents are larger for reaction with 4-nitrobenzyl mesylate than with the corresponding triflate.Selectivities were determined over a range of rate constants of ca. 1E4 for nucleophiles and ca. 1E5 for 4-nitrobenzyl sulfonates in 20:80 CH3CN/HOH (v:v) at 25 deg C, ionic strength 0.5 M (NaClO4).The slope of a correlation of log (kN/kHOH) for the two compounds is 1.12.Larger increases in selectivity of up to 11-fold were observed with more basic nucleophiles.The size of the additional increase is roughly proportional tothe basicity of the nucleophile, and it is suggested that reaction of the partially desolvated species may contribute to these differences.The results are described by a positive interaction coefficient pxy = s'/ log kHOH = s1g/ log knuc = 0.026.No significant change in selectivity of p-nitrobenzyl tosylate, nosylate, and triflate toward substituted anilines was observed over a 5-6-fold range of amine reactivity.The values of βnuc = 0.31 and 0.26 for the reactions of substituted anilines and aliphatic amines, respectively, with 4-nitrobenzyl tosylate do not differ significantly (70:30 EtOH/HOH (v:v), 25 deg C).The tosylate anion is a stronger nucleophile than water toward 4-nitrobenzyl triflate.It is concluded that SN2 substitution reactions do follow the Hammond postulate, or "Bema Hapothle", but that the small magnitude of the changes in selectivity requires the examination of a large range of reactivity for both the nucleophile and the substrate.
- Dietze, Paul,Jencks, William P.
-
p. 5880 - 5886
(2007/10/02)
-