- Danshensu derivativeS as well as preparation method and medical application thereof
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The invention discloses Danshensu derivatives as well as a preparation method and medical application thereof. The derivatives have a general structure as shown in a general formula (I) shown in the specification, wherein R1 represents OH or OCH3; R2 represents H or Ac; and R3 represents a first structure, a second structure or a third structure shown in the specification. Compared with a raw material medicine, the derivatives synthesized by the invention have the advantages that the fat solubility is increased, so that the derivatives can penetrate through the blood-brain barrier (BBB), the medicine stability is greatly improved, and the curative effect is further improved. Therefore, the derivatives disclosed by the invention can be applied to preparation of drugs for preventing, treating, treating and/or reducing the cerebral infarction volume of a patient, improving the balance coordination ability of the patient and other diseases, and a new therapeutic drug is provided for preventing and treating cerebrovascular or cranial nerve diseases.
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- Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
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Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.
- Kankanala, Jayakanth,Ribeiro, Carlos J. A.,Kiselev, Evgeny,Ravji, Azhar,Williams, Jessica,Xie, Jiashu,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
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supporting information
p. 4669 - 4682
(2019/05/17)
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- Interaction of α-Thymidine Inhibitors with Thymidylate Kinase from Plasmodium falciparum
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Plasmodium falciparum thymidylate kinase (PfTMK) is a critical enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides. N-(5′-Deoxy-α-thymidin-5′-yl)-N′-[4-(2-chlorobenzyloxy)phenyl]urea was developed as an inhibitor of PfTMK and has been reported as an effective inhibitor of P. falciparum growth with an EC50 of 28 nM [Cui, H., et al. (2012) J. Med. Chem. 55, 10948-10957]. Using this compound as a scaffold, a number of derivatives were developed and, along with the original compound, were characterized in terms of their enzyme inhibition (Ki) and binding affinity (KD). Furthermore, the binding site of the synthesized compounds was investigated by a combination of mutagenesis and docking simulations. Although the reported compound is indicated to be highly effective in its inhibition of parasite growth, we observed significantly lower binding affinity and weaker inhibition of PfTMK than expected from the reported EC50. This suggests that significant structural optimization will be required for the use of this scaffold as an effective PfTMK inhibitor and that the inhibition of parasite growth is due to an off-target effect.
- Chen, Mengshen,Sinha, Kaustubh,Rule, Gordon S.,Ly, Danith H.
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p. 2868 - 2875
(2018/05/14)
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- Metal-free synthesis of fluorinated indoles enabled by oxidative dearomatization
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Nitrogen heterocycles are found in a majority of approved small-molecule pharmaceuticals, and the number of approved fluorinated drugs is increasing each decade. Therefore, new approaches for accessing fluorinated nitrogen heterocycles are of great significance. A novel, scalable, and metal-free method for accessing a wide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore, the indole products contain a 3-trifluoroacetyl group, which can be exploited to access a plethora of useful functional groups.
- Vitaku, Edon,Smith, David T.,Njardarson, Jon T.
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supporting information
p. 2243 - 2247
(2016/02/18)
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- NEW ISOINDOLINE OR ISOQUINOLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I): (I) wherein Het, R3, R4, R5, R7, R8, R9, T, p, p', q, and q' are as defined in the description are pro-apoptotic agents useful in the treatment of cancers and of a
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Page/Page column 48
(2015/02/19)
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- Nonsolvent application of ionic liquids: Organo-catalysis by 1-alkyl-3-methylimidazolium cation based room-temperature ionic liquids for chemoselective N-tert-butyloxycarbonylation of amines and the influence of the C-2 hydrogen on catalytic efficiency
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1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently catalyze N-tert-butyloxycarbonylation of amines with excellent chemoselectivity. The catalytic role of the ionic liquid is envisaged as "electrophilic activation" of di-tert-butyl dicarbonate (Boc2O) through bifurcated hydrogen bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimidazolium cation and has been supported by a downfield shift of the imidazolium C-2 hydrogen of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim][NTf2]) from δ 8.39 to 8.66 in the presence of Boc2O in the 1H NMR and a drastic reduction of the catalytic efficiency with 1-butyl-2,3-dimethylimidazolium ionic liquids that are devoid of the C-2 hydrogen. The differential time required for reaction with aromatic and aliphatic amines has offered means for selective N-t-Boc formation during inter and intramolecular competitions. Preferential N-t-Boc formation with secondary aliphatic amine has been achieved in the presence of primary aliphatic amine. Comparison of the catalytic efficiency for N-t-Boc formation with a common substrate revealed that [bmim][NTf2] is superior to the reported Lewis acid catalysts.
- Sarkar, Anirban,Roy, Sudipta Raha,Parikh, Naisargee,Chakraborti, Asit K.
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experimental part
p. 7132 - 7140
(2011/10/08)
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- PEG-mediated facile protocol for N-Boc protection of amines
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We have reported an efficient and eco-friendly protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of PEG-400 at room temperature. The reaction gave excellent
- Siddaiah,Basha,Padma Rao,Viplava Prasad,Suryachendra Rao
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experimental part
p. 1127 - 1129
(2011/02/28)
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- HClO4-SiO2 as a new, highly efficient, inexpensive and reusable catalyst for N-tert-butoxycarbonylation of amines
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Perchloric acid adsorbed on silica-gel (HClO4-SiO2) was found to be a new, highly efficient, inexpensive and reusable catalyst for chemoselective N-tert-butoxycarbonylation of amines at room temperature and under solvent-free conditions. The Royal Society of Chemistry 2006.
- Chakraborti, Asit K.,Chankeshwara, Sunay V.
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p. 2769 - 2771
(2008/03/28)
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- Catalyst-free chemoselective N-tert-butyloxycarbonylation of amines in water
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Catalyst-free N-tert-butyloxycarbonylation of amines in water is reported. The N-t-Boc derivatives were formed chemoselectively without any isocyanate, urea, N,N-di-t-Boc, and O/S-t-Boc as side products. Chiral amines, esters of α-amino acids, and β-amino alcohol afforded optically pure N-t-Boc derivatives. Amino alcohol and 2-aminophenol afforded the N-t-Boc derivative without oxazolidinone formation. Selectivity was observed during competition of aromatic amine vs aliphatic amine, amine vs amino acid ester, amine vs amino alcohol, and primary amine vs secondary amine.
- Chankeshwara, Sunay V.,Chakraborti, Asit K.
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p. 3259 - 3262
(2007/10/03)
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- Indium(III) halides as new and highly efficient catalysts for N-tert-butoxycarbonylation of amines
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Indium(III) bromide and chloride efficiently catalysed the N-tert-butoxycarbonylation of amines with (Boc)2O at room temperature and under solvent-free conditions. Various aromatic, heteroaromatic and aliphatic amines were converted to N-tert-butylcarbamates in excellent yields in short times. Chiral amines, esters of α-amino acids and β-amino alcohols afforded optically pure N-t-Boc derivatives in high yields. The reactions were chemoselective and no competitive side reactions such as isocyanate, urea, and N,N-di-t-Boc formation were observed. Chemoselective conversion to N-tert-butylcarbamates took place with amino alcohols without any formation of oxazolidinones. Georg Thieme Verlag Stuttgart.
- Chankeshwara, Sunay V.,Chakraborti, Asit K.
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p. 2784 - 2788
(2008/02/05)
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- UREA DERIVATIVES AS KINASE MODULATORS
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The invention provides methods and compositions for treating conditions mediated by various kinases wherein derivatives of urea compounds are employed. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.
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