In this phytochemical investigation, a total of 16 previously undescribed and 27 known diterpene-related compounds were isolated from the endangered Chinese endemic conifer Podocarpus annamiensis. Podoannamiacids A (1) and B (2) represent the first examples of a new chemical class of diterpene-phenylpropanoid hybrids characterized by a unique 7'-phenyl-7',8'-dihydrobenzofuran unit. This structure is hypothesized to be biogenetically derived through the formation of newly generated C-12-C-8' and C-13-O-C-7' bonds via a free radical coupling reaction between a totarane unit and a phenylpropanoid moiety. The remaining previously undescribed compounds are structurally diverse diterpenoid monomers, including totarane-type compounds 3-9. Notably, annamiacids C (3) and D (4) feature a rare dihydro-pyrane fragment, while annamiacids E (5) and F (6) contain a dihydro-furan and a β,γ-unsaturated-γ-lactone motif, respectively. Compounds 10-14 are classified as abietane-type diterpenes, whereas compounds 15 and 16 are categorized as sempervirane-type and podocarpane-type diterpenes, respectively. Their chemical structures were elucidated using spectroscopic data analysis, GIAO NMR calculations combined with DP4+ probability analyses, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Liquiditerpenoic acid A (30) exhibited inhibitory activity against ATP-citrate lyase (ACL) with an IC50 value of 5.0 μM. Similarly, 18-hydroxysempervirol (40) inhibited acetyl-CoA carboxylase 1 (ACC1) with an IC50 value of 14.41 μM. Additionally, rakanmakilactone I (43) demonstrated anti-neuroinflammatory effects in BV-2 cells, reducing NO release by 21.4 % at a concentration of 20 μM. The above findings, along with previously reported totarane-O-abietane (44) and abietane-O-abietane dissymmetric bis-diterpenes (45), further expand the understanding of the structural diversity and medicinal potential of this endangered conifer, offering a promising strategy for its sustainable utilization and conversation. This approach not only positions the species as a potential source for treating metabolic diseases but also encourages the further protection of these fragile plant resources.

The construction of bicyclo[1.1.1.]pentanes (BCPs) typically require the cumbersome use of labile [1.1.1.]propellane in solution and involve multicomponent radical reactions, which commonly produce undesired by‐products that hinder the efficient construction of BCPs. In this paper, we present a catalyst‐free strategy by constructing an electron donor‐acceptor (EDA) complex utilizing the naturally electron‐deficient nature of BCP thianthrenium salt, which were irradiated with visible light to obtain trifluoromethyl‐BCP radicals through a SET process, subsequently reacted with various substituted quinoxalines. Moreover, the successful structural modification of drug molecule derivatives confirm the utility of this scheme in the field of drug discovery.

Inhibition of glycoside hydrolases has widespread application in the treatment of diabetes. Based on our previous findings, a series of dihydrofuro[3,2-b]piperidine derivatives was designed and synthesized from D- and L-arabinose. Compounds 32 (IC50 = 0.07 μM) and 28 (IC50 = 0.5 μM) showed significantly stronger inhibitory potency against α-glucosidase than positive control acarbose. The study of the structure–activity relationship of these compounds provides a new clue for the development of new α-glucosidase inhibitors.

A convenient and efficient reagent system of arylhydrazine salt‐selenium was developed to directly selenizing uracil preparation of 5‐selenium uracil. In the presence of this reagent, a variety of uracil/pyrimidine converts to their corresponding 5‐arylselanyluracils/5‐selenopyrimidine with good yield and high regioselectivity. Elemental selenium of commercially accessible, stable, affordable, and easy to use was used as the selenization reagent. This reaction is attractive and practical since there are no catalysts or ligands needed, and a wide range of functional groups can be tolerated.

A facile method was developed for the selective thioetherification of uracils using sulfonyl hydrazide as the thioetherification reagent.

Background: Rhizoma Paridis (RP) is a traditional Chinese herb used for the treatment of tumors, detoxification and hemostasia. Studies show the main components of RP are Polyphyllin I (PPI), polyphyllin VI (PPVI), and polyphyllin VII (PPVII). However, the pharmaco-mechanisms of these compounds are not clear. Objective: By used 1H nuclear magnetic resonance (1H-NMR) based metabolomics approach to identify the Anticancer effects of PPI, PPVI and PPVII in HepG2 cells. Methods: 1H nuclear magnetic resonance (1H-NMR) based metabolomics approach was applied to investigate the toxicological effect of PPI, PPVI, PPVII on HepG2 cells. Multivariate statistical analysis was employed to examine the metabolic changes and abnormal metabolic pathways, including Principal Component Analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA), and orthogonal PLS-DA (OPLS-DA). Results: The results showed that the effects of metabolic phenotypes were affected separately by PPI, PPVI, and PPVII. The metabolic phenotypes were also changed over time. The characteristic metabolites were varied by affecting different polyphylins, which were identified by the reconstructed OPLSDA loading plots. According to the characteristic metabolites, the mainly disturbed metabolic pathways were found, such as alanine, aspartate and glutamate metabolism, pyruvate metabolism, glycine, serine, and threonine metabolism. Conclusion: The current work could allow us to understand the therapeutic effect of RP in metabolism. It also indicated that RP would be a promising candidate for liver cancer treatment.

An efficient [4 + 1] annulation reaction between in situ generated azoalkene intermediates and α-bromocarbonyls has been established. A series of skeletally diverse aza-heterocycles with a functionalized quaternary center were obtained in up to 89% yield under mild conditions.

A transition metal‐free synthesis of 2‐arylquinoxaline is achieved by using arylhydrazine salt as an aryl radical arylation reagent and air as an oxidant in the presence of K2CO3. This protocol features metal‐free, no additives, mild reaction conditions, environment friendly, and can be used to construct biologically active molecules containing 2‐phenylquinoxaline structure.

K2CO3-mediated [4+1] annulation reactions of N-acetyl hydrazones with bifunctional amino reagents are described, which provide an environmental-friendly strategy to construct 1,2,3-triazoles that does not employ metals, azides, organocatalysis, or oxidants. A series of substituted 1,2,3-triazole derivatives was prepared with good yields.

The chemical investigation of the EtOAc extract of the fresh flowers of Juglans regia L. resulted in a new α-tetralonyl glucoside (1) and two known glucosides (2-3). The structure of the new compound was determined by extensive 1D and 2D NMR spectroscopic analysis and HRESIMS. The biological evaluation of the obtained glucosides showed that compound 1 and 3 displayed good antioxidant and antibacterial activities. These two compounds were identified as the main functional molecules in the fresh flowers of Juglans regia L.

A novel bis-indole alkaloid was isolated from the flowers of Rauvolfia Yunnanensis Tsiang. Its structure was elucidated as 10,11´- dimethoxy-11,10´-bis-[N(a)-methyl deacetyldeformyl- 1,2- dihydro akuammiline(2β)] (1) on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as HRESI-MS and comparison with data from the literature. The bis-indole alkaloid displayed more potent antihypertension activity and much lower hepatotoxicity in vivo than Reserpine.

A rapid, simple and mild process for the dehydration of aldoximes to give the corresponding nitriles, which utilizes SO2F2 as an efficient reagent, has been developed. A variety of (hetero) arene, alkene, alkyne and aliphatic aldoximes proceeded with high efficiency to afford nitriles in excellent to quantitative yields with great functional group compatibilities in acetonitrile under ambient conditions. Furthermore, an eco-friendly synthetic protocol to access nitriles from aldehydes with ortho-, meta-and para-nitrile groups was also described in aqueous methanol by using inorganic base Na2CO3, and a one-pot synthetic strategy to generate nitriles from aldehydes was proved to be feasible.

Background: Carcer is one of the most common diseases that endanger human health and even lives in the world today. As it reported, lung, breast and colon cancers are most common in the developing and under developed countries. Fortunately, several therapeutic regimes have been successfully approached for fighting cancer nowadays. Osimertinib (AZD9291), approved in 2015 by the FDA, as the third-generation inhibitors were designed to conquer the severe drug resistance for nonsmall-cell lung cancer. However, the emergence of new drug resistance of AZD9291 called for more potent new drugs. In order to design more potent new molecular entities, introduction of a new skeleton, such as 1,3-thiazole, to modified AZD9291 might gain better results. Herein, we reported the synthesis and biological evaluation of eighteen thiazole-2-carboxamide derivatives in this paper. Methods: All synthesized target compounds were evaluated for their growth inhibitory activity against two human tumor cell lines in vitro via using CCK-8 assay. Based on the in vitro potency in the assays, a lead compound was selected for in vivo studies of toxicity and chemotherapeutic efficacy. Results: The reported functionalized thiazole-2-carboxamide derivatives displayed potency against both of the two cell lines at low mu M concentrations. Compound 6f displayed significant anti-proliferative activity against both human lung cancer cell line and breast cancer cell line with IC50 values 0.48 mu M and 3.66 mu M, respectively. And compound 6f showed potent in vivo efficacy with tumor inhibition of 84.3% at a dosage of 10 mg/Kg. Conclusion: A series of novel thiazole-2-carboxamide derivatives were designed and synthesized. Several synthesized thiazole-2-carboxamide derivatives showed potent efficacy against both human lung cancer cell line and breast cancer cell line in vitro. And a lead compound 6f was proved to be well tolerated and potent in vivo efficacy compared to the positive control AZD9291.

An enzymic synthesis of glutathione-everolimus is reported. This process has been optimized and scaled up with high reproducibility and yields, which will facilitate the development of such conjugate. The stability of the conjugate supported that this prodrug can be prepared into lyophilized solid, which is to be reconstituted with 0.9% sodium chloride for injection before intravenous infusion. And the results of species-related drug release experiment displayed that the performance of the conjugate in human plasma, rat and monkey was similar. Moreover, the in vivo efficacy of glutathione-everolimus in the treatment of renal cell carcinoma was investigated in detail. The conjugate was proved to be an effective, safe and well-tolerated injectable prodrug in the treatment of renal cell carcinoma. The results indicated that three times injection with a high dosage in 1 week can achieve much better in vivo efficacy, and no obvious toxic response was observed.

A novel water-soluble everolimus prodrug, glutathione-everolimus, was designed and synthesized by introducing an endogenous tripeptide with an acetyl as the linker. The improvement in water solubility allowed the conjugate to be developed into an injectable drug. The results of biological evaluation in vitro and in vivo suggested that the prodrug was more effective and long acting than everolimus. Meanwhile, the pharmacokinetics study in vivo confirmed that the delivery of everolimus through the injection of the prodrug can overcome the low bioavailability of oral everolimus.

Background: Instability of the macrolide, high toxicity and water insolubility of epothilone B derivatives limit their application as clinical injectable drugs. For example, PEGlated epothilone B was reported to ameliorate its water solubility and stability, and cyclodextrins polymer (CDP) was also used to drug delivery of epothilones. However, ectogenic polymers may cause lots of potential adverse reactions because of incompatibility with human body. Glutathione, a water-soluble endogenous tripeptide, plays an important role in the biological systems and involves multiple cellular functions, which seems to be a preferred compound for drug delivery. Thus, this paper report here the synthesis and evaluation of glutathione-epothilone B.Methods: Derivatization of epothilone B at 3-hydroxyl group and 7-hydroxyl group by coupling with a lincker, alpha-iodoacetic acid, generated a epothilone B-iodoacetic acid derivative, which reacted with glutathilone to give glutathione-epothilone B. The water-solubility of the conjugate was measured. And the in vitro inhibitory activity to cancer cells and toxicity of the conjugate was evaluated by MTT assay. The stability of the conjugate in phosphate buffer saline and in human serum was studied, respectively, to support the results of the in vitro evaluation.Results: The solubility in water of the conjugate, glutathione-epothilone B, was remarkably improved to at least 4000 times greater than that of epothilone B. According to the results of the in vitro evaluation, the conjugate exhibited potent inhibitory activity to human liver cancer cells (HepG2 cells), which was slightly more potent than the lead compound epothilone B. Meanwhile, the toxicity of the conjugate was much lower than that of epothilone B. Releasing epothilone B of the conjugate was observed in human serum, which was completed in about 8 hours. And the conjuate was more stable in the pH 7.4 phosphate buffer saline. We believed that the introduction of glutathione can not only increase the stability of epothilone B, but also lead to reduced toxicity.Conclusion: This paper reported that the successful synthesis of a more stable and water-soluble pro drug of epothilone B, glutathione-epothilone B, which exhibited better inhibitory activity to human liver cancer cells (HepG2 cells). Moreover, the reported conjugate showed much lower toxicity to primary human hepatocyte than epothilone B.

The cover picture shows the stereoselective synthesis of various N-substituted iminosugars from D-xylose derivative. As is well known, iminosugars are potential glycosidase inhibitors, which have great potential as drugs to treat various diseases such as diabetes, Gaucher's disease, HIV infection and so on. Many examples indicate that N-substituted groups affect the bioactivity of iminosugars. An efficient and simple method was described for synthesis of N-substituted iminosugars via intramolecular Michael addition reaction. A series of N-alkyl substituted iminosugars C-glycosides were synthesized in good yields with high stereoselectivity. The stereochemistry of the final product was determined by 1H NMR and H-H-COSY. The coupling constants showed the trans-configuration between C-1 and 3′-OBn. More details are discussed in the article by Shao et al. on page 361–364.

To investigate hepatotoxic constituents, a new cycloartane-type triterpenoid ketone together with four known components was isolated from rhizomes of Curculigo orchioides. The structures of five compounds were elucidated on the basis of spectroscopic methods, including 1D and 2D NMR, and single-crystal X-ray diffraction analysis. Their hepatotoxicity effects in human hepatic cell line HL-7702 were tested for the first time.

A series of new N-alkyl-3-hydroxypiperidine derivatives containing a five-membered hemiketal were synthesized from 1-C-acetylmethyl sugars. Based on the stereochemistry of the products obtained, a plausible mechanism is illustrated. A new approach to the hemiketal, which has undergone hydrogenation in the presence of Pd/C and beta-elimination and intramolecular cycloaddition with 1% NaOMe in methanol, is reported.

AbstractTitle compounds (II) containing a five‐membered hemiketal are stereoselectively synthesized from acetylmethyl sugars (I).