- Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization
-
Aim: Cytarabine is an efficient anticancer agent for acute myelogenous leukemia, but with short plasma half-life and rapid deamination to its inactive metabolite. The aim of this study was to design and synthesize novel cholic acid-cytarabine conjugates to improve its pharmacokinetic parameters. Methods: The in vitro stability of novel cholic acid-cytarabine conjugates was investigated in simulated gastric and intestinal fluid, mouse blood and liver homogenate using HPLC. The portacaval samples of the conjugates were examined in male Sprague-Dawley rats using LC/MS, and in vivo distribution was examined in male Kunming mice using LC/MS. Antitumor activities were tested in HL60 cells using MTT assay. Results: Cholic acid-cytarabine compounds with four different linkers were designed and synthesized. All the four cholic acid-cytarabine conjugates could release cytarabine when incubated with the simulated gastric and intestinal fluid, mouse blood and liver homogenate. The conjugates 6, 12, and 16 were present in the portacaval samples, whereas the conjugate 7 was not detected. The conjugates 6 and 16 showed high specificity in targeting the liver (liver target index 34.9 and 16.3, respectively) and good absorption in vivo, as compared with cytarabine. In cytarabine-sensitive HL60 cells, the conjugates 6, 12, and 16 retained potent antitumor activities. Conclusion: Three novel cholic acid-cytarabine conjugates with good liver-targeting properties and absorption were obtained. Further optimization of the conjugates is needed in the future.
- Chen, Dan-Qi,Wang, Xin,Chen, Lin,He, Jin-Xue,Miao, Ze-Hong,Shen, Jing-Kang
-
-
Read Online
- Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation
-
Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the β-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.
- Moshikur, Rahman Md,Ali, Md. Korban,Wakabayashi, Rie,Moniruzzaman, Muhammad,Goto, Masahiro
-
p. 3108 - 3115
(2021/07/31)
-
- Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma
-
Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e–7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
- Zhou, Ruolan,Fang, Shaoyu,Zhang, Minmin,Zhang, Qingsen,Hu, Jian,Wang, Mingping,Wang, Chongqing,Zhu, Ju,Shen, Aijun,Chen, Xin,Zheng, Canhui
-
supporting information
p. 349 - 352
(2019/01/04)
-
- Synthesis of ergosterol peroxide conjugates as mitochondria targeting probes for enhanced anticancer activity
-
Inspired by the significant bioactivity of ergosterol peroxide, we designed and synthesized four fluorescent coumarin and ergosterol peroxide conjugates 8a-d through the combination of ergosterol peroxide with 7-N,N-diethylamino coumarins fluorophore. The cytotoxicity of synthesized conjugates against three human cancer cells (HepG2, SK-Hep1, and MCF-7) was evaluated. The results of fluorescent imaging showed that the synthesized conjugates 8a-d localized and enriched mainly in mitochondria, leading to significantly enhanced cytotoxicity over ergosterol peroxide. Furthermore, the results of biological functions of 8d showed that it could suppress cell colony formation, invasion, and migration; induce G2/M phase arrest of HepG2 cells, and increase the intracellular ROS level.
- Bu, Ming,Li, Hongling,Wang, Haijun,Wang, Jing,Lin, Yu,Ma, Yukun
-
-
- Resveratrol amino acid ester derivative and preparation method thereof
-
The invention discloses a resveratrol amino acid ester derivative and a preparation method thereof, and belongs to the technical field of fine chemical substance synthesis. The structure of the resveratrol amino acid ester derivative is represented by a formula shown in the description. The resveratrol amino acid ester derivative is synthesized from resveratrol, R amino acid, R' alcohol, dichlorosulfoxide and di(p-nitrobenzene) carbonate with 4-dimethylaminopyridine (DMAP) as a catalyst and acetonitrile as a solvent, wherein the R amino acid is one of alpha-alanine, beta-alanine and gamma-aminobutyric acid, and the R' alcohol is one of methanol, ethanol and n-propanol. The technical problem that resveratrol is difficult to preserve is solved, the pharmacological toxicity introduced by a resveratrol substituent group is lowered, and the resveratrol amino acid ester derivative has the pharmaceutical effects of resveratrol and amino acid. It is expected that the above novel compound playsa great role in beauty treatment and production of fatigue-relieving and blood pressure-lowering medicines.
- -
-
Paragraph 0059; 0076-0077
(2019/07/04)
-
- Selective oxidation of amines to aldehydes or imines using laccase-mediated bio-oxidation
-
An efficient and practical chemo-enzymatic aerobic oxidation in water of benzylamines to obtain aldehydes or imines is described. Laccase from Trametes versicolor was chosen as biocatalyst, and TEMPO (radical 2,2,6,6-tetramethylpiperidine 1-oxyl) as mediator. A study on the pH dependence of the aqueous medium allowed us to realise a fine tuning on product selectivity. Under our optimized reaction conditions, the bio-oxidation of a series of primary, secondary and cyclic amines has been achieved.
- Galletti, Paola,Funiciello, Federica,Soldati, Roberto,Giacomini, Daria
-
p. 1840 - 1848
(2015/06/02)
-
- First and convergent synthesis of hybrid sulfonophosphinopeptides
-
Figure Presented Hybrid sulfonophosphinopeptides were first and convergently synthesized in satisfactory to good yields via the Mannich-type reaction of N-protected 2-aminoalkanesulfonamides, aromatic aldehydes, and aryldichlorophosphines and subsequent aminolysis with amino esters.
- He, Fengdan,Meng, Fanhua,Song, Xiuqing,Hu, Wenxiang,Xu, Jiaxi
-
supporting information; experimental part
p. 3922 - 3925
(2009/12/05)
-
- Synthesis and cytotoxic properties of new fluorodeoxyglucose-coupled chlorambucil derivatives
-
Frequently used in the treatment of malignant cells, alkylating agents, like most anticancer substances, produce adverse side effects caused by the toxicity of the agents toward normal tissues and lose efficiency through poor distribution to target sites.
- Reux, Bastien,Weber, Valerie,Galmier, Marie-Josephe,Borel, Michele,Madesclaire, Michel,Madelmont, Jean-Claude,Debiton, Eric,Coudert, Pascal
-
p. 5004 - 5020
(2008/12/21)
-
- Conjugates of 2-fluoro-2-deoxy-glucose and their uses as anti cancer agents
-
The present invention relates to compounds of general formula (I): wherein: - R1, R2 and R3 mean, independently from the others, an hydrogen atom or an optionally substituted lower alkyl, a (C1-C7)acy
- -
-
Page/Page column 24-25
(2008/06/13)
-
- THIAZOLYL-DIHYDRO-CHINAZOLINE
-
Disclosed are compounds of general formula (I), wherein the groups A, R1, R2, Ra and Rb have the meanings given in the claims and specification, the tautomers, racemates, enantiomers, diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts, solvates and hydrates thereof, and processes for preparing these thiazolyl-dihydro-quinazolines and the use thereof as pharmaceutical compositions.
- -
-
Page/Page column 26
(2008/06/13)
-
- Lipases in β-dipeptide synthesis in organic solvents
-
A number of β-dipeptides were prepared by two-step lipase-catalyzed reactions where N-acetylated β-amino esters were first activated as 2,2,2-trifluoroethyl esters with Candida antarctica lipase B (CAL-B). The activated esters were then used to acylate a
- Li, Xiang-Guo,Kanerva, Liisa T.
-
p. 5593 - 5596
(2007/10/03)
-
- AZAARENE DERIVATIVES
-
A compound represented by the general formula: wherein X1 represents a nitrogen atom or a group represented by the formula -CR10=; X2 represents a nitrogen atom or a group represented by the formula -CR11=; Y represents an oxygen atom or the like; R1 represents a C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12b or the like; R2 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like; R3, R4, R5, R6, R7, R8, R10 and R11 each independently represent a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, or the like; R9 represents a group represented by the formula -NR16aR16b or the like; and R12a, R12b, R16a and R16b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, a salt thereof, or a hydrate of the foregoing.
- -
-
Page/Page column 57-58
(2008/06/13)
-
- Solid-phase synthesis of benzimidazole libraries biased for RNA targets
-
An efficient and highly versatile synthesis of two libraries 1(x,y) and 2-Ar(x,y,z) or 2-R2(x,y,w) based on the privileged benzimidazole scaffold is described. Our design is aimed at obtaining molecules, biased for binding to RNA targets, by in
- Vourloumis, Dionisios,Takahashi, Masayuki,Simonsen, Klaus B.,Ayida, Benjamin K.,Barluenga, Sofia,Winters, Geoffrey C.,Hermann, Thomas
-
p. 2807 - 2811
(2007/10/03)
-
- Tetracyclic benzimidazole derivatives and combinatorial libraries thereof
-
The present invention relates to novel tetracyclic benzimidazole derivative compounds of the following formula: wherein R1to R10have the meanings described in here. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing tetracyclic benzimidazole derivative compounds.
- -
-
-
- Triptycene analogs
-
This invention provides analogs of triptycene which are useful as anticancer drugs, as well as for other uses. The potency of these compounds is in a similar magnitude as daunomycin, a currently used anticancer drug. Each compound of the invention produces one or more desired effects (blocking nucleoside transport, inhibiting nucleic acid or protein syntheses, decreasing the proliferation and viability of cancer cells, inducing DNA fragmentation or retaining their effectiveness against multidrug-resistant tumor cells).
- -
-
-
- Bis(pyrimidine)-based palladium catalysts: Synthesis, X-ray structure and applications in Heck-, Suzuki-, Sonogashira-Hagihara couplings and amination reactions
-
The synthesis of N,N-bis(pyrimid-2-yl)amine (1), N-acetyl-N,N-bis(pyrimid-2-yl)amide (2), N-norborn-2-ene-5-ylbis(pyrimid-2-yl)carbamide (4) is described. The Pd-complex N-acetyl-N,N-bis(pyrimid-2-yl)amine palladium dichloride (3) has been prepared from compound 2 and its X-ray structure has been determined. A polymer supported catalytic system (6) was prepared via ring-opening metathesis copolymerization of 4 with 1,4,4a,5,8,8a-hexahydro-1,4,5,8-exo-endo-dimethanonaphthalene (HDMN-6) and subsequent loading with PdCl2. Both the homogeneous and heterogeneous catalysts 3 and 6 were active in Heck-, Suzuki-, Sonogashira-Hagihara-type couplings and amination reactions using aryl iodides, bromides and chlorides.
- Buchmeiser, Michael R.,Schareina, Thomas,Kempe, Rhett,Wurst, Klaus
-
-
- Reduction of Azides with Zinc Borohydride
-
Zinc borohydride in 1,2-dimethoxyethane provides an efficient procedure for the reduction of organic azides.Aroyl, acyl, and arylsulfonyl azides readily undergo reduction at room temperatue to produce amides and sulfonamides in excellent yields; however, substitution with electron-withdrawing groups in the aroyl azides leads to the corresponding benzyl alcohols.Reduction of aryl and alkyl azides has also been achieved in high yields, under some modified conditions.
- Ranu, Brindaban C.,Sarkar, Arunkanti,Chakraborty, Rupak
-
p. 4114 - 4116
(2007/10/02)
-
- MICHAEL-TYPE ADDITION OF DIETHYL PHOSPHORAMIDATE TO α,β-UNSATURATED ESTERS
-
Michael-type addition of diethyl phosphoramidate to α,β-unsaturated esters occurs when the reactants are refluxed in toluene or xylene with an excess of potassium carbonate in the presence of tetrabutylammonium bromide (TBABr).Dephosphorylation of methyl and ethyl acrylate adducts leads to the respective β-alanine esters. Key words: Diethyl phosphoramidate; α,β-unsaturated esters; Michael-type addition; β-alanine esters; phase-transfer catalysis.
- Osowska-Pacewicka, K.,Zawadzki, S.,Zwierzak, A.
-
-
- Water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives
-
The invention relates to novel water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives, the method for making the same and their use as X-ray contrast agents for vasography, urography, myelography, artrography, fistulography and salpingography.
- -
-
-
- Reduction d'azides par la triphenylphosphine en presence d'eau : une methode generale et chimioselective d'acces aux amines primaires
-
The reaction of azides with one equivalent of triphenylphosphine in the presence of a slight excess of water in THF leads quantitatively to the corresponding primary amines.This transformation is chemoselective.
- Knouzi, Noureddine,Vaultier, Michel,Carrie, Robert
-
p. 815 - 819
(2007/10/02)
-
- Thiocarbonyl Olefination, IV. - Preparation of β-Amino Acids from N-(Acetyl)thioamides; Total Synthesis of Iturinic Acid
-
A new method for the synthesis of β-amino acids is described whose key step consists in the regioselective thiocarbonyl olefination of N-(acetyl)thioamides with methyl (triphenylphosphoranylidene)acetate.By this procedure, a straightforward synthesis of iturinic acid has been carried out for the first time.
- Slopianka, Marion,Gossauer, Albert
-
p. 2258 - 2265
(2007/10/02)
-