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In this work, we report the strategy of one-pot synthesis of protoberberine alkaloid derivatives via palladium-catalyzed cascade α-arylation and cyclization, which can afford the target molecules in moderate to excellent isolated yields using commercially available raw materials under solvent-free conditions. This protocol provides an efficient and convenient path to multisubstituted protoberberine derivatives. In addition, it can directly afford natural alkaloids.

Background Skin cutaneous melanoma (SKCM) is an aggressive form of skin cancer with an elevated risk of metastasis and high mortality rates. Current immunotherapies represented by immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD-1/L1, have achieved remarkable durable responses in SKCM treatment. Recent studies have highlighted the biological significance of iron metabolism modification in tumorigenicity and progression. However, there has been insufficient evidence to reveal the prognostic value of iron metabolism-related genes (IMRGs) in SKCM and its relationship with the immune microenvironment and the efficacy of immunotherapy. Methods In this study, we curated 85 iron metabolism-related genes and performed unsupervised consensus analysis to identify iron metabolism modification patterns and the IMRG signature in SKCM. We used the ssGSEA algorithms to quantify the infiltration levels of various immune cells. An IMRG scoring scheme based on the PCA algorithm was used to evaluate the iron metabolism modification patterns of individual tumors. Results We identified three distinct iron metabolism modification patterns among 685 SKCM samples, which were associated with different prognoses and biological pathways. Meanwhile, three distinct iron metabolism modification patterns of SKCM had different immune cell infiltration. Based on the IMRG score, SKCM patients can be divided into high and low score subgroups. Multivariate Cox regression analysis showed that the IMRG score was an independent prognostic indicator. It was concluded that patients with lower IMRG scores had prolonged survival time. We further proved that a lower IMRG score was correlated with PD-L1, PD-1, CTLA4 expression, and better immune responses. Conclusions Our study highlights that iron metabolism is significantly associated with prognosis and immune cell infiltration. What’s more, this analysis of different IMRG patterns in SKCM patients contributed to a deeper understanding of TME and provided new perspectives for predicting prognosis and designing individualized immunotherapy strategies for SKCM patients.

A facile strategy for the synthesis of isoxazoles has been efficaciously developed, which involves oxidation of propargylamines to the corresponding oximes followed by CuCl-mediated intramolecular cyclization of the latter. This protocol shows a straightforward way to construct a series of isoxazole cores with a wide range of functional group compatibility. Meanwhile, a gram-scale experiment and synthetic applications can be successfully operated.

Osimertinib is a highly potent and selective third-generation epidermal growth factor receptor (EGFR) inhibitor, which provides excellent clinical benefits and is now a standard-of-care therapy for advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, AZ5104, a primary toxic metabolite of osimertinib, has caused unwanted toxicities. To address this unmet medical need, we initiated an iterative program focusing on structural optimizations of osimertinib and preclinical characterization, leading to the discovery of a highly potent, selective, and orally efficacious deuterated EGFR-targeting clinical candidate, dosimertinib. Preclinical studies revealed that dosimertinib demonstrated robust in vivo antitumor efficacy and favorable PK profiles, but with lower toxicity than osimertinib. These preclinical data support further clinical development of dosimertinib for the treatment of NSCLC. Dosimertinib has received official approval in China to initiate the phase I clinical trial (registration numbers: CXHL2000060 and CXHL2000061).

(±)-Sodium5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP, 1a), derived from L-3-n-butylphthalide (L-NBP), has been reported to protect the brain from stoke and has been approved by CFDA in Phase I-II clinical trials. However, it remains to be investigated whether 1a may exhibit any cardioprotective effect on ischemia-reperfusion (I/R) injury. In the current study, C57BL/6 and ICR mice were pretreated with 1a, and myocardium I/R were then performed. We found that 1a not only significantly reduced the infarct size and improved cardiac contractile function after acute MI/R in both species, but also protected hearts from chronic MI-related cardiac injury. Mechanically, we found that 1a physically binds to 12/15-LOX-2 using molecular docking. The shRNA-mediated 12/15-LOX-2 knockdown almost completely blocked the protective effect of 1a. Our findings, for the first time, strongly indicate that 1a may serve as a potent and promising cardioprotective agent in treatment of I/R related injury, at least partially through targeting 12/15-LOX-2.

A facile asymmetric total synthesis of (+)-aspidospermidine has been developed, which is accomplished in 11 steps in an overall yield of 9.6%. Key steps involve a palladium-catalyzed enantioselective decarboxylative allylation to install the quaternary carbon stereocenter and a highly efficient reductive amination–carbonyl reduction–dehydration–intramolecular conjugate addition cascade to build the cis D-ring.

PurposeTo study the influence of Monaco 5.4 treatment planning system (TPS) on the dosimetry of radiotherapy for nasopharynx carcinoma (NPC) under the condition of different segment shape optimization (SSO) times.MethodsFifteen patients with T3-4N0-2M0 stage nasopharyngeal carcinoma were enrolled, and each case was designed with SSO of 3, 5, 7 and 10 times respectively. The dose results of the target area and the major organs at risk (OAR) were statistically analyzed by DVH statistics; moreover, the isodose lines of 70Gy, 60Gy and 54Gy were intercepted at the same plane in the transverse, coronal and sagittal views and the segment shapes were compared at the angle of 30°, 120°, 240° and 330° in beam eye view (BEV); In addition, optimization time (OT), delivery time (DT), segments# and MU# were obtained and analyzed by optimization console; the plans were verified and analyzed by using ArcCheck phantom.ResultsFor target area D2, the results of the SSO7 group and the SSO10 group were similar and both better than those of SSO3 and SSO5 groups, and the D2 results of the SSO3 group were notable higher than those of the other three groups; for the major OARs, the results of the maximum dose of spinal cord, brain stem, and lens and the mean dose and V30 of parotid glands showed the same trend. It showed that SSO7 and SSO10 share similar dose results, too which are notable better than the similar dose results shared by SSO3 and SSO5; in the dose deprogram distribution of 70Gy, 60Gy and 54Gy, partial 70Gy dose spillover occurred in both groups SSO3 and SSO5 and it was more obvious in group SSO3. While there was a no significant dose spillover in group SSO7 and group SSO10; in the sub-field alignment comparison under the same angle, the alignment became more complicated and the sub-fields were smaller as the number of SSO increased; the results of segment#, MU# and plan delivery time between different SSO groups were slightly different, while the plan optimization time changed significantly. The difference between group SSO3 and group SSO10 was more than 500s; the results were compared in ArcCheck, there was no significant difference between the groups.ConclusionsThe user-defined SSO function of Monaco 5.4 TPS effectively balances the relationship between plan design efficiency and plan quality. When SSO is 7, it is better value for efficiency and quality in clinical radiotherapy for nasopharyngeal carcinoma.

A novel solvent-free, TfOH-promoted decyanative cyclization approach for the synthesis of 2,1-benzisoxazoles has been developed. The reactions are complete instantly at room temperature and result in the formation of the desired 2,1-benzisoxazoles in a 34-97% isolated yield.

In preclinical and phase I and II clinical studies, 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) displays a potent and long-lasting inhibition of HIV-1 infection. To investigate its mechanism of action, we compared it with the well-documented lamivudine (3TC). Pharmacokinetic studies revealed that the intracellular retention of FNC triphosphate in peripheral blood mononuclear cells was markedly longer than that of the 3TC triphosphate. FNC selectively enters and is retained in HIV target cells, where it exerts long-lasting prevention of HIV-1 infection. In addition to inhibition of HIV-1 reverse transcription, FNC also restores A3G expression in CD4+ T cells in FNC-treated HIV-1 patients. FNC binds to the Vif-E3 ubiquitin ligase complex, enabling A3G to avoid Vif-induced ubiquitination and degradation. These data reveal the mechanisms underlying the superior anti-HIV potency and long-lasting action of FNC. Our results also suggest a potential clinical application of FNC as a long-lasting pre-exposure prophylactic agent capable of preventing HIV infection.

Tanshinones are a class of bioactive compounds present in the Chinese herbal medicine Danshen (Salvia miltiorrhiza Bunge), containing among others, abietane diterpene quinone scaffolds. Chemical synthesis and biological activity studies of natural and unnatural tanshinone derivatives have been reviewed in this article.

Coronavirus disease 2019 (COVID‐19) has spread worldwide. To date, no specific drug for COVID‐19 has been developed. Thus we performed this randomized, open‐label, controlled clinical trial (ChiCTR2000029853) in China. A total of 20 mild and common COVID‐19 patients were enrolled and randomly assigned to receive azvudine and symptomatic treatment (FNC group), or standard antiviral and symptomatic treatments (control group). The mean times of the first nucleic acid negative conversion (NANC) of 10 patients in the FNC group and 10 patients in the control group were 2.60 (SD 0.97; range 1–4) days and 5.60 (SD 3.06; range 2–13) days, respectively (p = 0.08). The mean times of the first NANC of 4 newly diagnosed subjects in the FNC group and 10 subjects in the control group were 2.50 (SD 1.00; range 2–4) days and 9.80 (SD 4.73; range 3–19) days, respectively (starting from the initial treatment) (p = 0.01). No adverse events occurred in the FNC group, while 3 adverse events occurred in the control group (p = 0.06). The preliminary results showed that FNC treatment in the mild and common COVID‐19 may shorten the NANC time versus standard antiviral treatment. Therefore, clinical trials of FNC treating COVID‐19 with larger sample size are warranted.

The treatment of bromo homoallyl pyrrolyl/indolyl ketone derivatives with Pd(OAc)2 in the presence of PPh3 and Cs2CO3 in DMF resulted in the formation of tetrahydroindolones and tetrahydrocarbazolones in moderate to good isolated yields.

Starting from common intermediate methyl 1-hydroxy-9H-carbazole-3-carboxylate, synthetic routes toward murrayaquinone A, olivacine, and N-methylcalothrixin B were developed.

The interactions of human haemoglobin (HHb) with 5-epi-taiwaniaquinone G (G1) and one structural analogue of 5-epi-taiwaniaquinone G (G2) systematically by UV–vis absorption spectroscopy and fluore...

We presented a cesium carbonate promoted cascade reaction of N-tosyl-2-(2-bromophenylacetyl)pyrroles with DMF to synthesize dihydropyrrolizino[3,2-b]indol-10-ones. The transformation involved three successive bond formations without the aid of an exogenous transition metal catalyst or ligand.

The synthesis of 2-tetralone analogues via the palladium-catalyzed intramolecular α-arylation of 2-(2-bromoaryl)-1,3-dicarbonyl compounds has been described.

We report the structural optimization of tanshinone IIA, a natural product which possesses anti-tumor properties but low water-solubility, weak antiproliferative activity and poor PK properties. A new series of ring A/C/D modified tanshinone analogues were synthesized and studied for their antiproliferative capacities against six human cancer cell lines. SAR study revealed that ring A cleavage of tanshinone IIA led to improved anti-cancer activity. Introduction of a methoxy group to the phenyl ring could enhance the anti-cancer activity even further. Compound 2f with methoxy group at C-8 position was selected as an early lead with IC50 values of 0.28–3.16 μM against six tested cell lines. 2f could bind to tubulin colchicine site, inhibit tubulin assembly and disrupt the normal formation of microtubule networks. Cellular mechanistic studies revealed that 2f induced apoptotic cell death of A549 cells in a dose-dependent manner. In vitro investigations showed that 2f impeded the tubule-formation of HUVECs and potently inhibited the proliferation, migration and invasion of A549 cells as well as HUVECs. Furthermore, the in vivo anti-angiogenic effect of 2f was confirmed via a zebrafish model test. The satisfactory physicochemical property and metabolic stability of 2f, as well as improved water-solubility, further suggested that 2f could serve as a promising tubulin inhibitor and anti-angiogenic agent.

An efficient and general reductive heteroarylation approach toward the synthesis of bisindolylmethane, bispyrrolylmethane, and indolylpyrrolylmethane derivatives has been developed. Thus, treatment of acylpyrrole or acylindole derivatives with indoles or pyrroles in the presence of a combination of sodium borohydride and acetic acid resulted in the formation of the title compounds in moderate to excellent isolated yields.

Condensation of methyl 2-acylbenzoates with 2-arylethanamines or 2-acylanilines in the presence of trifluoroacetic acid resulted in the formation of isoindolo[1,2-a]isoquinolines or isoindolo[2,1-a]quinolines, respectively, in moderate to excellent isolated yields.

On treatment with Pd(OAc)2 and K2CO3, a variety of 3-aryl-2-(2-bromoallyl)-1,3-dicarbonyl compounds went through a monodearoylative dimerization reaction to provide polysubstituted [3]dendralenes in moderate to good isolated yields.

A unique strategy toward the synthesis of polysubstituted indolizines has been developed. When 2-pyridinyl-2-(2′-bromoallyl)-1-carboxylates were treated with Cs2CO3, the starting material went through a methylenecyclopropane ring formation/opening cascade, and the corresponding indolizines were obtained in moderate to good yield as a single regioisomer.

Yang Liu,1–3 Dan Li,2 Xinhong Guo,2 Haiwei Xu,2 Zhi Li,2 Yanling Zhang,2 Chuanjun Song,4 Ruhan Fan,2 Xing Tang,1,* Zhenzhong Zhang2,* 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 3Department of Pharmaceutics, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan, Zhengzhou, 4Department of Organic Chemistry, College of Chemistry andMolecular Engineering, ZhengzhouUniversity, Zhengzhou, People’s RepublicofChina *These authors contributed equally tothis work Abstract: We synthesized a pH-responsive conjugate of 10-hydroxycamptothecin-thiosemicarbazide-linear polyethylene glycol 2000 (PEG2000). The conjugate was confirmed by matrix-assisted laser desorption time of flight mass spectrometry, 1H NMR, and 13C NMR. The water solubility of the prodrug was increased by over 3,000 times; much longer body circulation time, higher tumor-targeting ability, and reduced toxicity were observed, compared with commercial 10-HCPT injection. The linker contains a pH-sensitive hydrazone bond, which breaks under low pH conditions in the tumor microenvironment. The conjugates showed good stability in phosphate-buffered saline (pH 7.4) and rat plasma. This amphiphilic conjugate could self-assemble into nanosized micelles of 80–100 nm. Cytotoxicity assay results indicate significantly higher efficacy of the conjugate (IC50 [half maximal inhibitory concentration] =0.117 µM on SW180 cells) than 10-HCPT solution (IC50 =0.241 µM on SW480 cells). Cellular uptake analysis suggested its rapid internalization and nuclear transport. Pharmacokinetic analysis of the conjugates demonstrated that the conjugate circulated for a longer time in the blood circulation system (T2/1 =10.516±1.158h) than did 10-HCPT solution (T2/1 =1.859±1.385 h), and that it also enhanced the targeting and mean residence time (MRT0–inf =39.873±4.549 h) in the tumor site, compared with 10-HCPT (MRT0–inf =9.247±1.026 h). Finally, the conjugate demonstrated an increased tumor growth inhibition effect (TIR =82.66%±7.175%) in vivo and lower side effects than 10-HCPT (TIR =63.85%±5.233%). This prodrug holds great promise in improving therapeutic efficacy and overcoming multidrug resistance. Keywords: 10-hydroxycamptothecin, conjugate, controlled release, prodrug, pH-responsive, hydrazone

8-Azanebularine analogues display interesting antiviral, antitumour and biochemical activities. However, typical glycosylation of 8-azapurines always resulted in the desired products in low yields due to the lack of stereo- and regioselectivity of the glycosylation reaction. Herein, a concise synthetic route toward 8-azanebularine analogues has been developed. Key steps involve a copper-catalyzed 1,3-dipolar cycloaddition of a 1-β-azido sugar moiety with ethyl 3-bromopropiolate and a palladium-catalyzed cascade amidine arylation-intramolecular ester amidation reaction to build the hypoxanthine structural motif. This protocol affords a facile methodology for the synthesis of a series of novel 8-azanebularine analogues from the readily accessible 1-β-azido sugar moiety under mild conditions.

The alkaloids containing a carbazole nucleus are an established class of natural products with wide range of biological activities. A combination of thermodynamic and enzymatic activity studies provides an insight into the recognition of Clausine E by the fat mass and obesity-associated protein (FTO). The binding of Clausine E to FTO was driven by positive entropy and negative enthalpy changes. Results also indicated that the hydroxyl group was crucial for the binding of small molecules with FTO. The structural and thermodynamic information provides the basis for the design of more effective inhibitors for FTO demethylase activity.

Microtubules are essential for the mitotic division of cells and have been an attractive target for antitumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In the past few years, tubulin-colchicine binding site, as one of the three binding pockets including taxol-, vinblastine- and colchicine-binding sites, has been focused on to design tubulin-destabilizing agents including inhibitors, antibody-drug conjugates and degradation agents. The present review is the first to cover a systemic and recent synopsis of tubulin-colchicine binding site agents. We believe that it would provide an increase in our understanding of receptor-ligand interaction pattern and consciousness of a series of challenges about tubulin target druggability.

Hepatitis B virus (HBV) is a global health problem requiring more efficient and better tolerated anti-HBV agent. In this paper, a series of novel 2′-deoxy-2′-fluoro-2′-C-methyl-β- d -arabinofuranosyl 8-azanebularine analogues (1 and 2a) and N4-substituted 8-azaadenosine derivatives (2b-g) were designed, synthesized and screened for in vitro anti-HBV activity. Two concise and practical synthetic routes were developed toward the structural motif construction of 2′-deoxy-2′-fluoro-2′-C-methyl-β- d -arabinofuranosyl 8-azainosine from the ribonolactone 3 under mild conditions. The in vitro anti-HBV screening results showed that these 8-azanebularine analogues had a significant inhibitory effect on the expression of HBV antigens and HBV DNA at a concentration of 20 μM. Among them, halogen-substituted 8-azaadenosine derivative 2g displayed activities comparable to that of 3TC. In particular, 2g retained excellent activity against lamivudine-resistant HBV mutants.

The first total synthesis of carbazole alkaloids lansine F and clauemarazole D is described. The spectroscopic data of the synthetic molecules were identical to those displayed by the natural products, thus confirming the accuracy of the proposed structures.

2-Cyclopentenone derivatives have been efficiently synthesized from 5-bromo-5-hexen-2-ones via palladium-catalyzed intramolecular carbonyl α-alkenylation followed by double-bond migration under mild reaction conditions.

Conjugated alternative donor–acceptor type pyrrol-pyridazyl-triazolyl-pyridine N-heterocyclic systems were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction of pyrrol-pyridazylacetylene with azidopyridines.

We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.

The interactions between human serum albumin (HSA) and 5-epi-taiwaniaquinone G (G2) or its isomeride (G1) was investigated by fluorescence, UV–visible absorption, resonance light scattering, synchronous fluorescence spectroscopy and 3D spectroscopy under mimic physiological conditions in combination with molecular modeling. The results revealed that G1 and G2 caused the fluorescence quenching of HSA by the formation of G1-HSA and G2-HSA complex, respectively. The binding constants and thermodynamic parameters at three different temperatures were obtained. Hydrophobic and electrostatic interactions played a role in the binding process of HSA and G1. Van der Waals force and hydrogen bond interaction played a role in the binding process of HSA and G2. Results showed that G2 was the stronger quencher and the position of methyl influenced the binding process between HSA and G1 (G2).

Fe(II) and α-ketoglutarate-dependent fat mass and obesity associated protein (FTO)-dependent demethylation of m⁶A is important for regulation of mRNA splicing and adipogenesis. Developing FTO-specific inhibitors can help probe the biology of FTO and unravel novel therapeutic targets for treatment of obesity or obesity-associated diseases. In the present paper, we have identified that 4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol (CHTB) is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner. The identification of the novel small molecule offers opportunities for further development of more selective and potent FTO inhibitors.

Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, PhI(OCOCF3)2, resulted in the formation of 1-pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salts has also been described.

A novel synthetic route toward tanshinone IIA has been developed. Key steps involve a base mediated furan ring formation, and an acyloin condensation reaction to construct the ortho-quinone ring.

Seven novel 4-amino acid derivative substituted pyrimidine nucleoside analogues were designed, synthesized, and tested for their anti-CVB3 activity. Initial biological studies indicated that among these 4-amino acid derivative substituted pyrimidine nucleoside analogues, 4-N-(2′-amino-glutaric acid-1′-methylester)-1-(2′- deoxy-2′-β-fluoro-4′-azido)-furanosyl-cytosine 2 exhibited the most potent anti-CVB activity (IC50 = 9.3 μM). The cytotoxicity of these compounds has also been assessed. The toxicity of compound 2 was similar to that of ribavirin.