摘要：
As a disease closely related to the metabolic syndrome, diabetes has become a public health issue that severely affects many people’s quality of life. The search for novel anti-diabetic agents remains the cornerstone to control this challenging disease. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin and leptin signaling pathways, has turned out to be a potential target of type II diabetes mellitus (T2DM) and obesity. In recent years, the development of novel anti-diabetic drugs based on PTP1B inhibitors has captured the attention of many researchers. Thiazole, a five-membered heterocycle containing sulfur and nitrogen atoms, has been considered as an essential core skeleton for various active compounds. Furthermore, thiazolidines, representing a series of compounds with saturated thiazole rings, widely exist in natural products and synthetic compounds with a variety of pharmacological activities. Here, we focus on the emphasis of PTP1B in diabetes and the development of PTP1B inhibitors based on thiazole and thiazolidine derivatives in the past decade. Many PTP1B inhibitors and their chemical structures, selectivity, potency, and structure-activity relationship have been elaborated. The great majority of PTP1B inhibitors containing thiazole and thiazolidine moieties described in this review exhibit preferable activities, which would be of importance for the rational design and efficient application of PTP1B inhibitors with anti-diabetes activity.
期刊：
Organic Process Research & Development,2020年24(8):1364-1372 ISSN：1083-6160
通讯作者：
Zheng, Xing;Jiang, Zhong-Xing
作者机构：
[Wu, Tingjuan; Chen, Kexin; He, Shuangyan; Liu, Xiaohe; Zheng, Xing] Univ South China, Dept Pharm, Grp Lead Compound, Hengyang 421001, Hunan, Peoples R China.;[Jiang, Zhong-Xing; Wu, Tingjuan; Chen, Kexin] Wuhan Univ, Hubei Prov Engn & Technol Res Ctr Fluorinated Pha, Sch Pharmaceut Sci, Wuhan 430071, Peoples R China.
通讯机构：
[Zheng, Xing] U;[Jiang, Zhong-Xing] W;Univ South China, Dept Pharm, Grp Lead Compound, Hengyang 421001, Hunan, Peoples R China.;Wuhan Univ, Hubei Prov Engn & Technol Res Ctr Fluorinated Pha, Sch Pharmaceut Sci, Wuhan 430071, Peoples R China.
关键词：
monodisperse poly(ethylene glycol)s;PEGylation;small molecular drug;prodrug;drug development
摘要：
Poly(ethylene glycol)s (PEGs) are the most used polymers in biomedicine, and their so-called “stealth” effects are the “gold standard” for biomaterials. However, the polydispersity in regular PEGs hampers their biomedical application, especially in modification of small molecular drugs (SMDs). To address this issue, many synthetic strategies for monodisperse PEGs (M-PEGs) have recently been developed. More importantly, M-PEGs have been successfully employed to modify SMDs, and the crucial roles of M-PEGs in PEGylated SMDs have been discovered in many cases. Herein we summarize the strategies for the synthesis of M-PEGylated SMDs, including Movantik, NKTR-181, polidocanol, propofol, and camptothecin, and the important roles of M-PEGs in optimizing the physicochemical properties, bioavailability, and therapeutic efficacy of SMDs. M-PEGylation is a convenient and effective strategy to develop novel SMDs, especially on the basis of marketed drugs. This review may shed light on the rational design and efficient synthesis of new M-PEGylated SMDs.
摘要：
Background: Oleanolic Acid (OA) is a ubiquitous product of triterpenoid compounds. Due to its inexpensive availability, unique bioactivities, pharmacological effects and non-toxic properties, OA has attracted tremendous interest in the field of drug design and synthesis. Furthermore, many OA derivatives have been developed for ameliorating the poor water solubility and bioavailability. Objective: Over the past few decades, various modifications of the OA framework structure have led to the observation of enhancement in bioactivity. Herein, we focused on the synthesis and medicinal performance of OA derivatives modified on A-ring. Moreover, we clarified the relationship between structures and activities of OA derivatives with different functional groups in A-ring. The future application of OA in the field of drug design and development also was discussed and inferred. Conclusion: This review concluded the novel achievements that could add paramount information to the further study of OA-based drugs.
作者机构：
[Jiang, Zhong-Xing; Wang, Xuemeng; Yang, Zhigang] Wuhan Univ, Wuhan, Peoples R China.;[Li, Yu; Zhou, Xin; Chen, Shizhen] Chinese Acad Sci, Wuhan, Peoples R China.;[Wu, Tingjuan; Zheng, Xing] Univ South China, Hengyang, Peoples R China.
通讯机构：
[Zhou, Xin] C;[Jiang, Zhong-Xing] W;Chinese Acad Sci, Wuhan, Peoples R China.;Wuhan Univ, Wuhan, Peoples R China.
摘要：
In biomedicine, PEGylation is one of the most successful strategies to modify the physicochemical and biological properties of peptides, proteins, and other biomacromolecules. Because of the polydisperse nature of regular PEGs and limited PEGylation strategies, it is challenging to quantitatively fine-tune and accurately predict the properties of biomacromolecules after PEGylation. However, such fine-tuning and prediction may be crucial for their biomedical applications. Herein, some monodisperse PEGylation strategies, including backbone PEGylation, side-chain PEGylation, and highly branched PEGylation, have been developed. In a comparative fashion, the impact of PEGylation strategies and monodisperse PEG sizes on the physicochemical and biological properties, including lipophilicity, thermosensitivity, biocompatibility, plasma stability, and drug delivery capability, of peptidic polymers has been quantitatively studied. It was found that the physicochemical and biological properties of PEGylated peptidic polymers can be quantitatively fine-tuned and accurately predicted through these monodisperse PEGylation strategies. After the comparative study, a side-chain monodisperse PEGylated peptidic polymer was chosen as fluorine-19 magnetic resonance and fluorescence dual-imaging traceable drug delivery vehicle. Our study may not only promote the transformation of PEGylation from an empirical technology to a quantitative science but also shed light on the rational design of PEGylated biomaterials and pharmaceutics.
通讯机构：
[Zheng, Xing; Zhang, Xingang] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hunan Prov Key Lab Tumor Microenvironm Respons Dr, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.;Univ Chinese Acad Sci, Key Lab Organofluorine Chem, Ctr Excellence Mol Synth, Shanghai Inst Organ Chem,Chinese Acad Sci, 345 Lingling Lu, Shanghai 200032, Peoples R China.
摘要：
A nickel-catalyzed tandem reaction of N-vinylamides with arylboronic acids and bromodifluoroacetate has been developed. The use of amide carbonyl as a chelating group efficiently furnishes a series of protected alpha,alpha-difluoro-gamma-amino acid esters. The reaction can also extend to bromoacetate and 2-bromomalonate. The advantages of this protocol are high functional group tolerance and a broad substrate scope, including a variety of N-vinylamides. In particular, the use of removable amide carbonyl groups provides potential opportunities for applications in peptide chemistry and protein engineering.
通讯机构：
[Zheng, Xing] U;[Wang, Ruowen] S;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.;Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Inst Mol Med,State Key Lab Oncogenes & Related Ge, Shanghai 00240, Peoples R China.
关键词：
Amino acids;Prodrug;SuFEx;Fluorosulfate
摘要：
Sulfur (VI) Fluoride Exchange (SuFEx) chemistry is proposed as a new generation of click chemistry with potential in drug discovery and biological study. Herein we report a simple and convenient approach to synthesize amino acid derivatives functionalized with aryl fluorosulfonyl group from a simple building block. Promoted by 1,1'-Carbonyldiimidazole (CDI), methyl protected amino acids and other amines were efficiently functionalized with SO2F by the reaction with 4-((fluorosulfonyl)oxy)benzoic acid giving fluorosulfonylated amides (FSAs) as products. We also demonstrated that FSAs are useful building blocks in drug discovery. The conjugation of FSA with pharmaceutical phenols by SuFEx efficiently introduced amino acid moiety into target molecule, providing a series of prodrugs with diverse property. (C) 2020 Elsevier Ltd. All rights reserved.
摘要：
Camptothecin, which represents a class of natural products with high anticancer activity, suffers low water solubility which hampers its clinic application. To address this issue, monodisperse polyethylene glycols were employed to modify this class of natural products, including Camptothecin, 10-Hydroxycamptothecin, and SN38. Through selective modification with a series of monodisperse polyethylene glycols, 31 Camptothecin derivatives, including 9 ethers and 22 carbonates, were prepared using a macrocyclic sulfate-based strategy with high efficacy. Monodisperse polyethylene glycols modification provided the Camptothecin derivatives with high purity and fine-tunable water solubility. Through the physicochemical and biological assays, a few novel prodrugs with good solubility, cytotoxicity, and valuable drug release profile were identified as promising anticancer drug candidates.
摘要：
A novel amphiphilic supramolecular polymer (ASP) with rigid linear main chain has been constructed by the co-assembly of a rigid amphiphilic monomer and cucurbit[8]uril (CB[8]) in water, driven by CB[8]-based host-guest interactions. The ASP could further self-assemble into well-defined architectures including nanotubes and 2D films, depending on its concentration. Moreover, pH-responsive behavior of the ASP was also observed. (C) 2019 Elsevier Ltd. All rights reserved.
摘要：
Flavan-3-ols are a series of natural products widely present in plants and show versatile biological activities. The structures of such compounds are characterized by owing two adjacent chiral centers and three rings. Their interesting structures and promising biological activities have driven increasing research developments toward the preparation of enantioenriched flavan-3-ols. This review summarizes the recent approaches for the asymmetric synthesis of chiral flavan-3-ols from two strategies in the construction of chiral centers. The key steps in the synthetic protocol involve Sharpless asymmetric dihydroxylation, Shi asymmetric epoxidation and Sharpless asymmetric epoxidation.
通讯机构：
[Tang, Guotao] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.
摘要：
According to the pharmacophore combination principle, a set of new 3,4,5-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
摘要：
Chrysin, a flavonoid, has played a great role in the fields of anticancer, antibacterial, and antiviral drug discovery. A large number of chrysin derivatives have been synthesized recently. The fluorine atom represents an important substituent group for a great number of natural products and pharmaceuticals. Taking into account the importance of both chrysin and the fluorine atom in medicinal chemistry, the synthesis of fluorine-containing chrysin derivatives has gained great interest. Chemically, the synthetic methods for these new chrysin derivatives have also been developed rapidly. In recent years, research on their synthesis has been focused on speeding up the reaction process by changing the catalyst. Biologically, the purpose of introducing fluorine into chrysin was to improve its lipophilicity, but today it is mainly focused on the enhancement and improvement of either its anticancer or antimicrobial activities by incorporating the special properties of fluorine atoms. In this review, synthetic methods for the introduction of fluorine atoms into chrysin are summarized, and their anticancer, antibacterial, antiviral, and hypoglycemic effects are discussed.
摘要：
Here, we report a new approach of on-resin peptide ligation using C-terminal benzyl ester as the stabilized precursor of thioester, which enables both N-terminal elongation and C-terminal peptide ligation on a Rink Amide resin. On-resin native chemical ligation and auxiliary-assisted peptide ligation were successfully achieved. This method is compatible to both protected and unprotected peptide fragments and has potential application in poor water-soluble peptide ligation.
