26348-61-8Relevant articles and documents
Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation
An, Yunfei,Dong, Yue,Liu, Min,Han, Jun,Zhao, Liyu,Sun, Bin
, (2020/11/13)
Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Squalene epoxidase (SE) and 14α-demethylase (CYP51) are considered as the important antifungal targets, they can show the synergistic effect on antifungal therapy. In the study, a series of active fragments were screened through the method of De Novo Link, and these active fragments with the higher Ludi_Scores were selected, which can show the obvious binding ability with the dual targets (SE, CYP51). Subsequently, three series of target compounds with naphthyl amide scaffolds were constructed by connecting these core fragments, and their structures were synthesized. Most of compounds showed the antifungal activity in the treatment of pathogenic fungi. It was worth noting that compounds 10b-5 and 17a-2 with the excellent broad-spectrum antifungal properties also exhibited the obvious antifungal effects against drug-resistant fungi. Preliminary mechanism study has proved these target compounds can block the biosynthesis of ergosterol by inhibiting the activity of dual targets (SE, CYP51). Furthermore, target compounds 10–5 and 17a-2 with low toxicity side effects also demonstrated the excellent pharmacological effects in vivo. The molecular docking and ADMET prediction were performed, which can guide the optimization of subsequent lead compounds.
Method for preparing Fmoc-Ser (tBu)-OH
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Paragraph 0061-0062, (2020/12/30)
The invention relates to a method for preparing Fmoc-Ser (tBu)-OH, and belongs to the technical field of medical intermediate chemical engineering. The technical problem to be solved by the inventionis to provide a method for preparing Fmoc-Ser (tBu)-OH. The method comprises the following steps: a, enabling Ser-OR. HCl to react with Fmoc-OSu, so as to obtain an Fmoc-Ser-OR solid; b, mixing the Fmoc-Ser-OR solid, tert-butyl acetate, perchloric acid and tert-butyl alcohol, reacting at 15-40 DEG C, regulating the pH value to 5-6, separating out a solid, filtering, washing and drying to obtain anFmoc-Ser (tBu)-OR solid; and c, hydrolysis: carrying out hydrolysis on the Fmoc-Ser (tBu)-ORsolid to obtain an Fmoc-Ser (tBu)-OH product. According to the method, the Fmoc group is introduced firstly, the racemization risk in the saponification process can be reduced, tert-butyl acetate, perchloric acid, tert-butyl alcohol and hydroxyl in Fmoc-Ser-OR are adopted for reaction when tert-butyl is introduced, operation is easy and controllable, safety is good, the obtained product is high in chiral purity and low in cost, the production steps can be effectively shortened, and the production efficiency and yield are improved; the method is suitable for modern industrial production.
Potent arylamide derivatives as dual-target antifungal agents: Design, synthesis, biological evaluation, and molecular docking studies
An, Yunfei,Dong, Yue,Han, Jun,Liu, Min,Liu, Xinyong,Sun, Bin
, (2020/03/27)
Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Ergosterol is an important structural component of the fungal cell membrane, its synthetases (squalene epoxidase (SE) and 14α-demethylase (CYP51)) are considered as the key points to block the ergosterol synthesis. In this study, we designed a series of dual-target arylamides derivatives based on the analysis of active sites (SE, CYP51). Subsequently, these target compounds were synthesized, and their antifungal activity was evaluated. Most of compounds demonstrate the potent antifungal activity against multiple Candida spp. and A. fum. In particular, the antifungal activities of compounds 10b and 11c are not only superior to positive control drugs, but also have significant inhibitory effects on drug-resistant fungi (C.alb. Strain100, C.alb. Strain103). Therefore, their action mechanism was further studied. Cellular uptake and electron microscopy observation showed that target compounds were able to enter fungal cytoplasmic region through free diffusion, and destroyed cell membrane structure. At the same time, preliminary mechanisms have demonstrated that they can affect the synthesis of ergosterol by inhibiting the activity of dual targets. It is worth noting that they also can exhibit excellent antifungal activity and low toxic side effects in vivo. Their ADMET properties and binding models were established will be useful for further lead optimization.
OLEIC ACID DERIVATIVES, PHARMACEUTICAL COMPOSITION OR FOOD COMPOSITION COMPRISING SAID OLEIC ACID DERIVATIVES, AND THEIR USES
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Page/Page column 35-36, (2019/12/25)
This invention relates to oleic acid derivative comprising a hydrophobic part C17H33 linked to a particular polar head part "A", especially for use as a medicament, for instance, for the treatment of a disorder caused by the GPR120 receptor and/or the CD36 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of said oleic acid derivative or of said pharmaceutical composition. The invention also relates to the use of said oleic acid derivative as a food composition.
Synthesis and Evaluation of Cyclic Acetals of Serine Hydroxylamine for Amide-Forming KAHA Ligations
Baldauf, Simon,Bode, Jeffrey W.
supporting information, p. 1273 - 1283 (2019/02/26)
The α-ketoacid-hydroxylamine (KAHA) ligation allows the coupling of unprotected peptide segments. The most widely used variant employs a 5-membered cyclic hydroxylamine that forms a homoserine ester as the primary ligation product. While very effective, m
Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors
Dong, Yue,Liu, Min,Wang, Jian,Ding, Zhuang,Sun, Bin
, p. 26302 - 26314 (2019/09/09)
Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment. Squalene cyclooxygenase (SE) and 14α-demethylase (CYP51) are considered to be important antifungal targets, and the corresponding pharmacophore models can be used to design and guide the discovery of novel inhibitors. Therefore, the common feature pharmacophore model (SE inhibitor) and structure-based pharmacophore model (CYP51 receptor) were constructed using different methods in this study. Then, appropriate organic fragments were selected and superimposed onto the pharmacophore features, and compounds 5, 6 and 8 were designed and produced by linking these organic fragments. It is noteworthy that compound 8 can simultaneously match the features of both the SE and CYP51 pharmacophores. Further analysis found that these compounds exhibit a potent antifungal activity. Preliminary mechanistic studies revealed that compound 8 could undergo dual-target inhibition (SE and CYP51) of Candida albicans. This study proved the rationale of pharmacophore models (SE and CYP51), which can guide the design and discovery of new antifungal inhibitors.
Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain
Pang, Chaohai,Luo, Jinhui,Liu, Chunhua,Wu, Xuejin,Wang, Dingyong
, (2018/05/04)
The synthesis of celastrol analogues containing amino acid ester at the C(29) position and their evaluation for cytotoxic activities in?vitro were reported. The MTT test showed that a set of derivatives with lower IC50 values than that of the positive control group cisplatin and the parent compound celastrol, which exhibited greater antiproliferative activities. The most potent title compounds 2a and 2e exhibited cytotoxic activities in?vitro against HeLa and A549 cell lines with IC50 values of 0.371 and 0.237?μm, 0.235 and 0.109?μm, respectively. The apoptosis assay demonstrated that 2a and 2e can induces of A549 cell apoptosis in low concentrations. These results showed that 2a and 2e may be promising for further research as antitumor agents.
Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies
Zhao, Dongmei,Zhao, Shizhen,Zhao, Liyu,Zhang, Xiangqian,Wei, Peng,Liu, Chunchi,Hao, Chenzhou,Sun, Bin,Su, Xin,Cheng, Maosheng
, p. 750 - 758 (2016/12/28)
Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal
Synthesis and characterization of tailorable biodegradable thermoresponsive methacryloylamide polymers based on l-serine and l-threonine alkyl esters
van Dijk, Maarten,Postma, Tobias M.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,van Nostrum, Cornelus F.,Hennink, Wim E.
experimental part, p. 2479 - 2485 (2011/10/09)
A series of monomers based on the methyl, ethyl, and isopropyl esters of Nα-(methacryloyl)-serine and -threonine were synthesized, and used in an AIBN-initiated radical polymerization reaction to yield polymers with an Mn ranging between 6.6 and 23.8 kDa. The newly synthesized polymers showed LCST behavior in aqueous solution that could be tailored by subtle variations of the hydrophobicity of the monomers to obtain a broad range of cloud points between 1.5 and >100°C. According to HPLC, the hydrolytic t1/2-values (pH 7.4 at 37°C) of the monomers were found to be 5, 12, and 40 days of the methyl, ethyl, and isopropyl esters, respectively, while the hydrolysis rate of poly[Nα-(methacryloyl)-Ser-OMe] and poly[Nα-(methacryloyl)-Thr-OMe] was found to be significantly lower compared to the corresponding monomers. In order to obtain thermoresponsive nanoparticles, Nα-(methacryloyl)-Thr-OEt was polymerized with (PEG monomethyl ether 5000)2-ABCPA as macroinitiator to yield an amphiphilic block co-polymer, poly[Nα-(methacryloyl)-Thr-OEt]-b-(PEG monomethyl ether 5000), which forms particles of 300 nm at a temperature higher than its cloud point of 24°C. Incubation at physiological conditions induced ester hydrolysis resulting in a destabilization of the particles making these particles suitable for drug delivery purposes.
Synthesis and cytotoxic evaluation of two novel anthraquinone derivatives
Sadeghi-Aliabadi, Hojjat,Tabarzadi, Maryam,Zarghi, Afshin
, p. 645 - 649 (2007/10/03)
The antitumor activity of dihydroxyanthracenediones such as mitoxantrone on a panel of cancer cell lines during the last 30 years, led investigators to synthesize thousands of anthracycline analogs and test their cytotoxicity to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. To achieve this, new synthesized congeners either have different side arms or have extra rings on their skeletons. Following these studies, we proposed total synthesis of 2-amino-N-[4-(2-amino-3-hydroxy-propionylamino)-9,10-dioxo-9, 10-dihydroanthracene-1-yl]-3-hydroxy-propionamide (V) and 6-amino-hexanoic acid [4-(5-amino-pentanoylamino)-9,10-dioxo-9,10-dihydro-anthracen-1-yl]-amide (VI). Acetylation of 1,4-diaminobenzene using acetyl chloride and reaction with phthalic anhydride under a Friedel-Crafts reaction and then cyclization gave 1, 4-diamino-anthraquinone. This compound was reacted with two amino acids (L-serine and 6-amino hexanoic acid) in their ester forms, using ethyl chloroformate as a coupling agent. Hydrolyzing esterified compounds gave their amino substituted derivatives. These compounds with diamine side arms are supposed to provide better intercalation with DNA. Synthesized novel ametantrone derivatives were tested against a panel of cancer cells (KB, Hela, MDA-MB-468 and K562), using MTT assay. The results showed that tested compounds inhibited the growth of cancer cells at micromolar concentrations. However, compound (VI) was more cytotoxic than compound (V) probably because of its longer side chains and better intercalation with DNA.
