104055-46-1Relevant articles and documents
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)
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.
Synthesis and Evaluation of Cyclic Acetals of Serine Hydroxylamine for Amide-Forming KAHA Ligations
Baldauf, Simon,Bode, Jeffrey W.
, p. 1273 - 1283 (2019)
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
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.
, p. 2479 - 2485 (2010)
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.
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)
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 cytotoxic evaluation of two novel anthraquinone derivatives
Sadeghi-Aliabadi, Hojjat,Tabarzadi, Maryam,Zarghi, Afshin
, p. 645 - 649 (2004)
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.
NovelN-transfer reagent for converting α-amino acid derivatives to α-diazo compounds
Lu, Guan-Han,Huang, Tzu-Chia,Hsueh, Hsiao-Chin,Yang, Shin-Cherng,Cho, Ting-Wei,Chou, Ho-Hsuan
supporting information, p. 4839 - 4842 (2021/05/25)
A novel universalN-transfer reagent for direct and effective transformation of α-amino ketones, acetamides, and esters to the corresponding α-diazo products under mild basic conditions has been developed. This one-step synthetic approach not only allows for generation of α-substituted-α-diazo carbonyl compounds from α-amino acid derivatives but also permits preparation of α-diazo dipeptides fromN-terminal dipeptides (32 examples, up to 91%).
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.
