Insight into Medicinal Chemistry Behind Traditional Chinese Medicines: p-Hydroxybenzyl Alcohol-Derived Dimers and Trimers from Gastrodia elata

From an aqueous extract of“tian ma”(the steamed and dried rhizomes of Gastrodia elata),ten new compounds gastrodiben-zins A−D(1−4)and gastrotribenzins A−F(5−10),along with known analogues(11−20),having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon-and/or ether-bonds,were isolated and characterized by spectroscopic data analysis.Meanwhile,the new compounds 5a,6a,8a,22,and 23,as well as the known derivatives 13a,14a,15,17−21,24,25,and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol.Methylation of 5a and 6a in methanol and ethylation of 6a,8a,13a,and 14a in ethanol produced 5 and 6 and 7,8,13,and 14,respectively.using ultra-performance liquid chromatography high-resolution electrospray ioniza-tion mass spectrometry(UPLC-HRESIMS)analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G.elata rhizome and“tian ma”extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time.In various assays,the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin,which are the main known active constituents of“tian ma”.These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G.elata rhizomes,demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines.

The medicinal chemistry of Urtica dioica L.:from preliminary evidence to clinical studies supporting its neuroprotective activity

Urtica dioica is a perennial herb from the family of Urticaceae that is commonly known as stinging nettle.This plant is widespread in Europe,Africa,America,and a part of Asia,as it adapts to different environments and climatic condi-tions.The leaves,stalk,and bark of U.dioica found applications in the field of nutrition,cosmetics,textile,pest control and pharmacology.In this connection,bioactive chemical constituents such as flavonoids,phenolic acids,amino acids,carotenoids,and fatty acids have been isolated from the plant.With this review,we aim at providing an updated and comprehensive overview of the contributions in literature reporting computational,in vitro,pre-clinical and clini-cal data supporting the therapeutic applications of U.dioica.Experimental evidence shows that U.dioica constituents and extracts can provide neuroprotective effects by acting through a combination of different molecular mecha-nisms,that are discussed in the review.These findings could lay the basis for the identification and design of more effective tools against neurodegenerative diseases.

Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

Anticancer Activities of Substituted Cinnamic Acid Phenethyl Esters on Human Cancer Cell Lines

Caffeic acid phenethyl ester (CAPE) and sixteen substituted cinnamic acid phenethyl esters were prepared via conventional procedures in order to test their in vitro anticancer activities by either MTT assay or SRB assay on six different human cancer cell lines. The results indicated that in the concentration of 10 μmol·L -1 the lead compound CAPE possessed anticancer activities against human HL 60, Bel 7402, and Hela cell lines, and two other compounds possessed potent anticancer activities against Bel 7402 and Hela cell lines.

Synthesis of Phenylpropanoid Glycoside Analogs

The regioselective acylation of unprotected phenylethyl glucoside withcinnamoyl chloride leads to 6-OH cin-namoylated glucoside. In this manner, thirteen phenylpropanoidglycoside analogs were designed and prepared. Their structure was confirmed by ~1H NMR and ^(13)CNMR spectra.

An Explorer of Chemical Biology of Plant Natural Products in Southwest China,Xiaojiang Hao

Xiaojiang Hao,who obtained Master Degree from Kunming Institute of Botany(KIB),Chinese Academy of Sciences(CAS)in 1985,and Doctor in Pharmacy degree in Pharmacy from Institute for Chemical Research,Kyoto University,in 1990,was born in Chongqing in July,1951.In 1991,he returned to KIB,CAS,as an Associate professor and served as the chair of the Department of Phytochemistry.In 1994,he was promoted to a full professor at the current institute.He served as the Deputy Director of KIB and the Director of Open Laboratory of Phytochemistry from 1995 to 1997,and the Director of KIB from 1997 to 2005.Professor Hao has published more than 450 peer-reviewed SCI papers,which have been cited over 6000 times.He has obtained one PCT patent and 23 patents in China.Due to his tremendous efforts,one candidate drug,phenchlobenpyrrone,has entered the Phase II clinical trail for the treatment of Alzheimer’s disease.Moreover,he won the First Prize of Natural Sciences in Yunnan Province for three times,and Ho Leung Ho Lee Fund Science and Technology Innovation Award in 2017.

Stem cell differentiation and human liver disease

Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,eff icient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the f ield and discuss the future potential and limitations of stem cell technology.

Methods, units and quality requirements for the analysis of haemoglobin A_(1c) in diabetes mellitus

The formation of glycohemoglobin, especially the hemoglobin A1c(Hb_(A1c)) fraction, occurs when glucose becomes coupled with the amino acid valine in the β-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970 s it has been known that diabetics display higher values of Hb_(A1c) because they have elevated blood glucose concentrations. Thus Hb_(A1c) has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement of Hb_(A1c), numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple minicolumn technique to the very accurate automated highpressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for Hb_(A1c) varied extensively between laboratories, therefore in United States and Canada working groups(WG) of the Diabetes Controls and Complications Trial(DCCT) were set up to standardize the Hb_(A1c) assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990 s, the International Federation of Clinical Chemistry and Laboratory Medicine(IFCC) appointed a new WG to plan a reference preparation and method for the Hb_(A1c) measurement. When the reference procedureswere established, in 2004 IFCC recommended that all manufacturers for equipment used in Hb_(A1c) assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation(CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the Hb_(A1c) assays, analytical problems, problems with the units in which Hb_(A1c) values are expressed, reference values, quality control aspects, target requirements for Hb_(A1c), and the relationship of the plasma glucose values to Hb_(A1c) concentrations. We also note that the acceptance of the mmol/mol system for Hb_(A1c) as recommended by IFCC, i.e., the new unit and reference ranges, are becoming only slowly accepted outside of Europe where it seems that expressing Hb_(A1c) values either only in per cent units or with parallel reporting of percent and mmol/mol will continue. We believe that these issues should be resolved in the future and that it would avoid confusion if mmol/mol unit for Hb_(A1c) were to gain worldwide acceptance.

Medicinal chemistry strategies in the discovery and optimization of HBV core protein allosteric modulators(2018-2022 update)

Despite the improving coverage of preventative vaccines,hepatitis B remains a severe global public health problem,with more than 250 million patients living with hepatitis B virus(HBV)infection.Current available therapies,including nucleos(t)ide analogs and peginterferon,can control HBV replication but fail to eliminate covalently closed circular DNA(cccDNA)and achieve a cure.The HBV core protein(Cp)is a well-conserved structural protein,self-assembling to form the viral capsid.It involves in or modulates almost every stage of the HBV lifecycle,which makes it an attractive target for the development of new anti-HBV therapies.HBV core protein allosteric modulators(CpAMs)have become a hotspot in recent years.Herein,we provide a concise report focusing on the various medicinal chemistry strategies involved in the latest research(2018-2022)of HBV CpAMs,including high throughput screening(HTS),virtual screening(VS),drug repositioning,natural products,substitution decorating approach,scaffold hopping,molecular hybridization,prodrug strategy and conformational constraint strategy,to provide guidance for further development of new and effective anti-HBV drugs.

Chemistry-led investigations into the mode of action of NAMPT activators,resulting in the discovery of non-pyridyl class NAMPT activators

The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

CHEMISTRY AND BIOACTIVITY OF POLYSACCHARIDES FROM TRADITIONAL CHINESE MEDICINE MAHUANG

The long-term clinical practice of traditional Chinese medicine(TCM)confirms its importance and essential role in the health care system in China,especially in the prevention and treatment of chronic diseases.TCM is the holistic medicine under the guidance of system theory,emphasizing harmony between human and nature,focusing on equilibrium and balance,and focusing on

Sequential dual-locking strategy using photoactivated Pt(Ⅳ)-based metallo-nano prodrug for enhanced chemotherapy and photodynamic efficacy by triggering ferroptosis and macrophage polarization

Selective activation of Pt(Ⅳ)prodrugs within tumors has emerged as a promising strategy in tumor treatment.Although progress has been made with photo-and ultrasound-activated Pt(Ⅳ)prodrugs,concerns remain over the non-specific activation of photosensitizers(PS)and the potential for phototoxicity and chemical toxicity.In this study,a sequential dual-locked Pt(Ⅳ)nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed.The Pt(Ⅳ)prodrug was prepared by conjugating PS-locked Pt(Ⅳ)to a polymeric core,which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug.Under acidic tumor microenvironment conditions,the metallo-nano prodrug undergoes dissociation of iron,triggering a reduction process in oxaliplatin under light irradiation,resulting in the activation of both chemotherapy and photodynamic therapy(PDT).Additionally,the prodrug could induce metallo-triggered ferroptosis and polarization of tumorassociated macrophages(TAM),thereby enhancing tumor inhibition.The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs,making it a promising new direction in cancer treatment.

Medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

The synthesis of benzoxaboroles and their applications in medicinal chemistry

Benzoxaborole,as a versatile scaffold,plays important roles in organic synthesis,molecular recognition and supramolecular chemistry.It is also a privileged structure in medicinal chemistry due to its desirable physicochemical and drug-like properties.Recently,benzoxaboroles were widely applied as antifungal,antibacterial,antiviral,anti-parasite,and anti-inflammatory agents.This review covers the properties,synthetic methods and applications of benzoxaboroles in medicinal chemistry.

Fluorine-containing drugs approved by the FDA in 2019

Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed.Therapeutic areas include schizophrenia,migraine,multiple sclerosis,insomnia,rheumatoid arthritis,anti-tuberculosis,breast cancer,lymphoma kinase inhibitor,serotonin receptor antagonist.New pharmaceuticals feature four examples of aromatic fluorine,three aromatic CF3 group,three aliphatic CF3 and one compound with aromatic CF3O group.Furthermore,among the new compounds,six are chiral and seven are derived from tailor-made amino acids.

Synthesis of Thioproline Salicylic Acid Samarium Complex and Microcalorimetric Study on Effects of the Complex on the Growth Metabolism of S. pombe Cells

The product from reaction of samarium chloride hexahydrate with salicylic acid and thioproline, [Sm（C7H503）2·（CaH6NO2S）]-2H20 （TSAS）, was synthesized and characterized by IR, elemental analysis and ther- mogravimatric analysis. Particularly, the effect of the compounds TSAS, SmCl3·6H2O, C7H6O3 and C4HTNO2S on the growth and metabolism of S. pombe by a TAM Air isothermal calorimeter at 32 ~C is also reported. The ther- mokinetic parameters, which included the microbial growth rate constant （x）, inhibition ratio （/） and half inhibition concentration （IC50）, were obtained. The results showed that all the compounds TSAS, SmC13.6H20, C7H603 and CaHTNO2S possessed the bi-directional biological effect and Hormesis effect. These stimulate the growth of the S. pombe at lower concentration, but inhibit the growth at higher concentration. The half inhibition concentrations （IC50） of TSAS, SmCl3·6H2O, CnH7NO2S and C7H603 were found to be 0.732, 0.746, 0.746 and 1.43 mmol·L-1, respectively. The inhibition ability of these compounds on the growth of the S. pombe has been observed to decrease in the order TSAS 〉 SmCl3·6H2O = CaH7NO2S〉C7H6O3. Moreover, the effect of TSAS on the growth and cytokinesis of S. pombe was investigated by cytomorphology and FT IR spectroscopy technique. The results indicated that TSAS had a direct impact on apoptosis, and could also inhibit the cell growth by reducing cytokinesis and the binding locations of drug （TSAS） in S. pombe cells could be the proteins and nucleic acid.