- A hypoxia-specific and mitochondria-targeted anticancer theranostic agent with high selectivity for cancer cells
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Herein, a novel soluble mitochondria-targeted theranostic compound, HMX-1, was presented, which was selectively activated under hypoxia with excellent mitochondria-targeting ability at the cellular level, accompanied by a dramatic increase in the fluorescence intensity. Moreover, its anti-cancer efficiency was certified both in vitro and in vivo.
- Hu, Mingxing,Yang, Chao,Luo, Yi,Chen, Fan,Yang, Fangfang,Yang, Shuping,Chen, Hao,Cheng, Zhiqiang,Li, Kun,Xie, Yongmei
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Read Online
- Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity
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Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2–6.2 μM and exhibited 5.0–18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy.
- Xie, Rui,Li, Yan,Tang, Pingwah,Yuan, Qipeng
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Read Online
- Synthesis and antiproliferative activity of some new DNA-targeted alkylating pyrroloquinolines
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Two novel DNA-direct alkylating agents, consisting of aniline mustard linked to an angular 3H-pyrrolo[3,2-f]quinoline nucleus, were synthetized and assayed for their in vitro antiproliferative activity. Simple convergent synthesis, consisting of separate preparation of 9-chloro-3H-pyrrolo[3,2-f] quinoline and p-amino-aniline derivatives, and following their linkage by substitution reactions 8a, b and 10, yielded the corresponding diol derivatives 7b and 9. Biological properties were evaluated with respect to cell growth inhibition, ability to form cross-links with DNA, and capacity to give rise to a molecular complex with the macromolecule for 7b, 8b, 9 and 10.
- Ferlin,Via, L. Dalla,Gia
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Read Online
- Host-guest interactions involving cyclodextrins: useful complementary insights achieved by polarimetry
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By means of simple polarimetry, we studied the binding abilities of native α-, β-, and γ-cyclodextrins toward a group of suitably chosen model guests. We were able to get reliable estimations of the binding constants K, spread over a wide range (from 3.7
- Lo Meo, Paolo,D'Anna, Francesca,Riela, Serena,Gruttadauria, Michelangelo,Noto, Renato
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Read Online
- Cyanine-based fluorescent indicator for mercury ion and bioimaging application in living cells
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A commercial cyanine dye IR-780 and a thioether-containing dicarboxylic acid ligand were used to construct the near-infrared fluorescent probe, which was used as a near-infrared fluorescent indicator for the determination of mercury ions in water and in living cells. This indicator displayed high specificity towards Hg2+ without any interference from other detecting species. Especially, the emission at 790 nm dramatically increased more than 25 times after interacting with Hg2+. The binding experiment showed that the indicator formed 1:1 complex with Hg2+. More, this indicator could be applied in the visualization of Hg2+ in living cells and measuring the Hg2+ concentration of tap-water sample.
- Li, Guangjin,Guan, Yihan,Ye, Fengying,Liu, Sheng Hua,Yin, Jun
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- Hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and preparation method thereof
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The invention discloses a hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The compound contains an alpha-ketoamide structure and a nitrogen mustard structure, can rapidly respond to H2O2, can be used as the nitrogen mustard anti-tumor pro-drug, has good response effect to H2O2, has high cell selectivity and small toxic and side effects, provides an effective, safe and highly selective anti-tumor drug, enriches the types of nitrogen mustard anti-tumor drugs, and has a good market prospect.
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Paragraph 0073; 0077-0079
(2019/10/17)
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- N nitrogen mustard derivatives, two N - (2 - chloroethyl) - 1, 4 - phenylenediamine - N' - sixteen-acyl and its preparation method
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The invention discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-hexadecanoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the reaction raw materials comprising the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of hexadecanoyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, conducting reaction at room temperature for 12 to 14 hours, sequentially performing washing, drying and normal-pressure distillation on the reaction liquid after the reaction is conducted completely, and purifying the distilled filter cake to obtain the product. The arylamine nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
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Paragraph 0044-0047; 0057-0060; 0070-0073
(2019/05/15)
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- A new BODIPY-based fluorescent “turn-on” probe for highly selective and rapid detection of mercury ions
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A new fluorescent sensor based on the BODIPY fluorophore and the carboxyl-thiol metal bonding receptor for Hg2+ was designed and synthesized. The sensor is highly selective for Hg2+ (about 630-fold fluorescence enhancement) over relevant competing metal ions, sensitive to ppb levels of Hg2+ (with detection limit of 5.7 nM), and fast response toward Hg2+ (within 30 s) in aqueous solution.
- Zhou, Baocheng,Qin, Siyao,Chen, Bo,Han, Yifeng
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supporting information
p. 4359 - 4363
(2018/11/06)
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- Two-photon fluorescent probe with Cu identification function as well as preparation method and application thereof
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The invention discloses a two-photon fluorescent probe with a Cu identification function as well as a preparation method and an application thereof. A structural formula of the two-photon fluorescent probe with a Cu identification function is show
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Paragraph 0042; 0043; 0044
(2017/09/01)
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- Nitrogen mustard compounds containing hydroxamic acid groups as well as preparation method and application of nitrogen mustard compounds
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The invention discloses nitrogen mustard compounds containing hydroxamic acid groups as well as a preparation method and an application of the nitrogen mustard compounds and relates to the field of medicinal chemistry. The compounds have the capability of inhibiting cancer cell proliferation, achieve the purpose of treating cancer and particularly have excellent cancer cell proliferation inhibition activity for inhibiting human cutaneous melanoma A375, human cervical carcinoma cells HeLa, human liver cancer cells HepG2, human lung cancer cells A549 and human colon cancer cells HCT116. The compounds have the structure shown in a general formula I, wherein X1, X2, X3, X4 and Z are defined in the specification.
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Paragraph 0049
(2017/07/20)
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- Nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-myristoyl-1,4-phenylenediamine and preparation method thereof
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The invention particularly discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-myristoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of myristyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, reacting at room temperature for 10 to 14 hours, washing the reaction liquid after the reaction is conducted completely, drying with anhydrous cupric sulfate, performing normal-pressure distillation, and purifying the distilled filter cake to obtain the product. The nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
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Paragraph 0045-0048
(2017/07/04)
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- Aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine and preparation method thereof
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The invention particularly discloses a structural formula and preparation method of an aryl nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-propionyl-1,4-phenylenediamine. The method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; adding the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in an ice water bath, stirring, and dropwisely adding a propionyl chloride-dichloromethane mixed solution into the reactor; after finishing the dropwise addition, removing the ice water bath, and reacting at room temperature for 4-14 hours; and after the reaction finishes, washing the reaction solution, drying with anhydrous cupric sulfate, carrying out atmospheric distillation, and purifying the filter cake. The aryl nitrogen mustard derivative can effectively lower the toxic and side effects of nitrogen mustards on the premise of enhancing the therapeutic index of the nitrogen mustards, and has the curative effects of killing germs and diminishing inflammation, thereby lowering the risk of complications caused by decrease in immunity of the patient after chemotherapy.
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Paragraph 0046; 0047; 0048; 0059; 0060; 0061; 0072-0074
(2017/08/29)
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- Nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-benzoyl-1,4-phenylenediamine and preparation method thereof
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The invention particularly discloses a structural formula of a nitrogen mustard derivative N,N-di(2-chloroethyl)-N'-benzoyl-1,4-phenylenediamine, and a preparation method thereof. The preparation method comprises the following steps: preparing N,N-di(2-chloroethyl)-1,4-phenylenediamine; putting the N,N-di(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine into a reactor, cooling in ice-water bath, stirring, dropwise adding a mixed solution of benzoyl chloride and dichloromethane into the reactor, removing the ice-water bath after addition, conducting reaction at room temperature for 8 to 14 hours, sequentially performing washing, drying and normal-pressure distillation on the reaction liquid after the reaction is conducted completely, and purifying the distilled filter cake to obtain the product. The arylamine nitrogen mustard derivative provided by the invention can effectively reduce the toxic and side effects of nitrogen mustard on the premise of enhancing the treatment index of the nitrogen mustard, and has sterilization and inflammation-diminishing curative effects to reduce the risk of complication caused by the fact that the immunity is reduced after a patient is subjected to chemical therapy.
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Paragraph 0045; 0046; 0047; 0048; 0059-0061; 0072-0074
(2017/08/28)
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- Arylamine nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-acetyl-1,4-phenylenediamine and preparation method thereof
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The invention specifically discloses a structural formula of an arylamine nitrogen mustard derivative N,N-bis(2-chloroethyl)-N'-acetyl-1,4-phenylenediamine and a preparation method of the derivative. The method comprises the following steps: preparing N,N-bis(2-chloroethyl)-1,4-phenylenediamine; filling a reactor with N,N-bis(2-chloroethyl)-1,4-phenylenediamine, dichloromethane and triethylamine, cooling in an ice-water bath, stirring, dropwise adding a mixed solution of acetyl chloride and dichloromethane into the reactor, removing the ice-water bath after dropwise adding, reacting at the room temperature for 2-14 hours, washing, drying and distilling after the reaction is completed, purifying the distilled filter cake, thereby obtaining the product. The arylamine nitrogen mustard derivative disclosed by the invention can effectively reduce the toxic or side effects of nitrogen mustard on the premise of enhancing the therapeutic index of the nitrogen mustard and has the curative effects of sterilizing and diminishing inflammation so as to reduce the risk of causing complications due to decrease in immunity after chemotherapy of a patient.
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Paragraph 0045-0048; 0061; 0074
(2017/08/29)
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- Pyrazolo [1, 5 - a] pyrimidine nitrogen mustard derivative and its preparation method and tumor therapeutic use
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The invention relates to pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or medical salts thereof, as well as application of the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or the medical salts thereof. The pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have the structure shown as the formula I. Pharmacological experiments show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have inhibiting effects on the proliferation of various tumor cells. Moreover, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are small in toxicity, have the advantages of selectivity on tumor cells, and are dual-functional anti-tumor drugs. Meanwhile, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are easy to synthesize, and the overall yields are high. All the advantages show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives have great potential of being anti-tumor drugs.
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Page/Page column 0100; 0101; 0102
(2017/08/02)
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- AZO MEDIATORS
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Azo compounds are disclosed that do not form azoxy dimers and that do not have any reactive nitroso groups. Also disclosed are use of the azo compounds as mediators in optical and electrochemical diagnostic methods, as well as detection reagents, kits and test elements that include such azo compounds and that can be used in the diagnostic methods.
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Paragraph 0098; 0099; 0100
(2017/01/02)
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- Copper(II)-catalyzed enantioselective intramolecular cyclization of N-alkenylureas
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The first Cu(II)-catalyzed highly enantioselective intramolecular cyclization of N-alkenylureas was developed for the concise assembly of chiral vicinal diamino bicyclic heterocycles. Facile removal of carbonyl group of the carbamido moiety allowed for ready access to enantioenriched cyclic vicinal diamines.
- Fu, Shaomin,Yang, Honghao,Deng, Yuanfu,Jiang, Huanfeng,Zeng, Wei,Li, Guoqiang
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supporting information
p. 1018 - 1021
(2015/03/30)
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- 2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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Page/Page column 130
(2012/05/20)
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- Synthesis and structure-analgesic activity relationships of a novel series of monospirocyclopiperazinium salts (MSPZ)
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A series of monospirocyclopiperazinium salts were designed and synthesized to search for a peripherally-acting analgesic drug with low side effects. Extensive SAR studies revealed that a suitable NR2R3 was critical for the analgesic activity, which might be beneficial to expose the cationic nitrogen to bind to the receptor, and possibly interact with the receptor via π-π interaction. Introduction of substituting group on the N4-phenyl ring could improve the activity, and the best position was the 4-position. Compound 14n showed more potent analgesic activity (63%, 20 μM/kg, sc) and holds promise for development as a mechanically new analgesic drug.
- Lin, Song-Wen,Sun, Qi,Ge, Ze-Mei,Wang, Xin,Ye, Jia,Li, Run-Tao
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supporting information; experimental part
p. 940 - 943
(2011/03/21)
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- TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS
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The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.
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Page/Page column 67
(2010/11/17)
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- Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use related applications
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The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.
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Page/Page column 30
(2010/11/30)
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- ENZYME ACTIVATED SELF-IMMOLATIVE N-SUBSTITUTED NITROGEN MUSTARD PRODRUGS
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This invention pertains to certain enzyme (CPG2) activated self-immolative nitrogen mustard prodrugs, which are useful in enzyme prodrug therapy (EPT), such as ADEPT and GDEPT, for the treatment of proliferative conditions, such as cancer, and which have
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- Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT).
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The suitability of 4-di(2-chloroethyl)aminoanilino-4-hydroxyphenethylaminomethanone 2 to act as a prodrug for melanocyte-directed enzyme prodrug therapy (MDEPT) is assessed. Thus its synthesis, ability to generate a cytotoxic agent upon exposure to tyrosinase, and stability within different sera are reported. A comparison is made to illustrate that the new urea prodrug 2 is a more suitable candidate for MDEPT than the corresponding carbamate prodrug 1.
- Jordan, Allan M,Khan, Tariq H,Malkin, Hugh,Osborn, Helen M I
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p. 2625 - 2633
(2007/10/03)
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- A very convenient dimethylamination of activated aromatic halides using N,N-dimethylformamide and ethanolamines
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A very convenient dimethylamination of activated aromatic halides was achieved by using N,N-dimethylformamide(DMF) and ethanolamines. p- Nitrochlorobenzene, 2-halopyridines, 2-chloroquinoline and 2-chloropyrimidine gave the corresponding dimethylamino substituted products when treated with DMF and diethanolamine in 80-92% yield.
- Cho, Yoon Hwan,Park, Jae Chan
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p. 8331 - 8334
(2007/10/03)
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- Hypoxia-Selective Antitumor Agents. 3. Relationships between Structure and Cytotoxicity against Cultured Tumor Cells for Substituted N,N-Bis(2-chloroethyl)anilines
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A series of aniline mustards with a wide range of electron-donating and -withdrawing substituents in the 3- and 4-positions has been synthesized and evaluated for cytotoxicity in cell culture to examine the potential of using nitro group deactivated nitrogen mustards for the design of novel hypoxia-selective anticancer drugs (Denny, W.A.; Wilson, W.R.J.Med Chem. 1986, 29, 879).Hydrolytic half-lives in tissue culture media, determined by bioassay against a cell line (UV4) defective in the repair of DNA interstrand cross-links showed the expected dependence on the Hammett electronic parameter, ?, varying from 0.13 h for the 4-amino analogue to >100 h for analogues with strongly electron-withdrawing substituents.Cytotoxic potencies in aerobic UV4 cultures showed a similar dependence on ?.This dependence predicted that the 4-nitroaniline mustard would be 7200-fold less potent than its potential six-electron reduction product, the 4-amino compound, in growth inhibition assays using a 1-h drug exposure.The measured differential was much lower (225-fold) because of the instability of the latter compound, but a differential of 17500-fold was observed in the initial rate of killing by using a clonogenic assay.The potential for formation of reactive mustards by reduction to the amine or hydroxylamine was demonstrated by the 4-nitroso compound, which had an aerobic toxicity similar to that of the amine.Although these features confirmed the original rationale, the 3-nitro- and 4-nitroaniline mustards had only minimal hypoxic selectivity against UV cells.Toxicity to hypoxic cells appears to be limited by the low reduction potentials of these compounds and consequent lack of enzymatic nitroreduction.However, this study has demonstrated that nitro groups can be used to latentiate aromatic nitrogen mustards and indicates that examples with higher reduction potentials could provide useful hypoxia-selective therapeutic agents.
- Palmer, Brian D.,Wilson, William R.,Pullen, Susan M.,Denny, William A.
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p. 112 - 121
(2007/10/02)
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- A NEW SYNTHESIS OF AROMATIC AND HETEROAROMATIC NITROGEN MUSTARDS VIA 3-PYRROLINES
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Reaction of aromatic and heteroaromatic halides with 3-pyrroline gives adducts which can be converted in a three-step process to nitrogen mustards.
- Palmer, Brian D,Denny, William A
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p. 601 - 610
(2007/10/02)
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