Divergent Total Syntheses of Lycorine Alkaloids via a Sequential C-H Functionalization Strategy.

A Pd-catalyzed one-pot sequential C-H functionalization strategy was utilized to prepare four lycorine alkaloids and one pseudo-lycorine alkaloid from the common intermediate 4. By switching the followed oxidative conditions of air, DMSO/H2O/I2, and DMSO/O2, based on the Pd(PPh3)4/K2CO3/toluene catalytic system, three key intermediates 12a, 12b, and 12c with different substitution patterns could be obtained in a well-controlled manner. As a result, four natural products γ-lycorane, hippadine, anhydrolycorinone, and anhydrolycorine as well as a pseudo-lycorine alkaloid Δ(4a,10b)-6-oxodihydrolycorine were successfully synthesized within 10 steps through this divergent route.

Discovery of acetophenone/piperazin-2-one hybrids as selective anti-TNBC cancer agents by causing DNA damage.

Twenty-five acetophenone/piperazin-2-one (APPA) hybrids were designed and synthesized based on key pharmacophores found in anti-breast cancer drugs Neratinib, Palbociclib, and Olaparib. Compound 1j exhibited good in vitro antiproliferative activity (IC50 = 6.50 µM) and high selectivity (SI = 9.2 vs HER2-positive breast cancer cells SKBr3; SI = 7.3 vs normal breast cells MCF-10A) against triple negative breast cancer (TNBC) cells MDA-MB-468. In addition, 1j could selectively cause DNA damage, inducing the accumulation of γH2AX and P53 in MDA-MB-468 cells. It also reduced the phosphorylation level of P38 and the expression of HSP70, which further prevented the repair of DNA damage and caused cells S/G2-arrest leading to MDA-MB-468 cells death.

Synthesis of C3'-Foused Aryl/Penta-1,4-Dien-3-One/Amine Hybrids as HSP90C-Terminal Inhibitors.

24 C3'-focused hybrids of aryl/penta-1,4-dien-3-one/amine (APDA) were designed and synthesized. Of these hybrids, 2 n demonstrated improved antiproliferative effects on HER2-positive breast cancer cells (SKBr3 and BT474) and triple-negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) with IC50 values ranging from 7.45 to 10.75 µM, but less toxicity to normal breast cells MCF-10A than the first generation of hybrid 1. Additionally, 2 n retained its ability to inhibit HSP90C-terminus, leading to the degradation of HSP90 client proteins HER2, EGFR, pAKT, AKT, and CDK4, without inducing a heat-shock response. Notably, 2 n also demonstrated improved thermostability compared to 1 and maintained in vitro metabolic stability in simulated intestinal fluid. These findings will provide a scientific basis for developing HSP90C-terminal inhibitors in the future.

The prognostic value of controlling nutritional status (CONUT) score-based nomogram on extranodal natural killer/T cell lymphoma patients.

Controlling nutritional status (CONUT) score as an original nutritional assessment tool can be used to assess the prognosis of patients with a variety of malignancies. However, the predictive power of CONUT in extranodal natural killer/T cell lymphoma (ENKTL) patients has never been demonstrated. Our retrospective multicenter study aimed to explore the prognostic value of CONUT in newly diagnosed ENKTL. A total of 1085 newly diagnosed ENKTL patients between 2003 and 2021 were retrospectively retrieved. Cox proportional hazard model was used to explore the prognostic factors of overall survival (OS). The survival rate of ENKTL was evaluated using Kaplan-Meier analysis, and log-rank test was applied to the difference between groups. We investigated the prognostic performance of CONUT, the International Prognostic Index (IPI), the Korean Prognostic Index (KPI), and the Prognostic Index of Natural Killer Cell Lymphoma (PINK) using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). The median age at diagnosis for the whole cohort was 47 years, and the male to female ratio was 2.2:1. The 5-year OS for all patients was 72.2%. Multivariable analysis showed that CONUT, age, bone marrow involvement, ECOG PS score, and Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL stage were identified as independent predictive factors for OS. Based on multivariable results, a prognostic nomogram was developed. Subgroup analysis demonstrated that patients with severe malnutrition had poorest clinical outcome. In addition, ROC curves and DCA analysis proved that compared with IPI, KPI, and PINK models, the CONUT score-based nomogram showed a better prognostic predictive efficiency of ENKTL. CONUT could effectively stratify the prognosis of ENKTL and the proposed nomogram based on CONUT was an effective prognostic model for prediction.

Design, synthesis, and anti-triple negative breast cancer activity of novel Toosendanin derivatives.

Toosendanin (TSN) is a natural anti-cancer compound that is isolated from the traditional Chinese herbal Melia toosendan Sieb et Zucc. However, the research effect of TSN in the treatment of Triple negative breast cancer (TNBC) is still far from ideal. In this work, we investigated TSN and its derivatives in terms of their actions against MDA-MB-231 and HCC1806 TNBC cell lines. The results indicated that TSN and its derivative 11 showed excellent antitumor activity. Preliminary mechanistic studies showed that both compounds TSN and 11 induced S-phase arrest and G2/M phase cell number decrease in HCC1806 cells. Also, TSN and 11 significantly reduced the protein level of the well-known cancer suppressor gene p53, reduced the phosphorylation of AKT and ERK, and also induced the accumulation of phosphorylated p38 and p21.

Development of actein derivatives as potent anti-triple negative breast cancer agents.

Actein is a natural triterpenoid glycoside, isolated from the rhizomes of Cimicifuga foetida, which have been demonstrated to be potential in the treatment of breast cancer previously. Herein, we described the design and synthesis of a series of actein derivatives as anti-triple negative breast cancer (TNBC) inhibitors. Of which, the most promising derivative 27 exhibited significant inhibitory activity against human TNBC cell lines HCC1806 and MDA-MB-231, with IC50 values of 2.78 and 9.11 µM, respectively. Structure-activity relationships of actein derivatives were also discussed. Moreover, preliminary mechanism investigation revealed that 27 significantly inhibited cancer cell proliferation via cell cycle arrest at S phase. In addition, western blot analysis showed that the activation of MAPK signaling pathway might contribute to derivative 27 induced cell death. Overall, these results indicate that 27 has the potential to be developed as a lead compound and compounds with the actein scaffold are a promising novel class of inhibitors to treat TNBC.

Chemical Synthesis Enables the Configurational Determination of Myristriol, a Highly Oxygenated Phenylpropanoid from Myristica fragrans Houtt.

A new phenylpropanoid, myristriol (1), along with 11 known ones were isolated from the seed kernel of Myristica fragrans Houtt. Their chemical structures were clearly elucidated by extensive spectroscopic analysis. In which, the relative configuration of 1 was finally determined as erythro-1 by comparison the NMR data of two synthetic erythro- and threo-diastereoisomers with that of natural 1.

Value of the prognostic nutritional index (PNI) in patients with newly diagnosed, CD5-positive diffuse large B-cell lymphoma: A multicenter retrospective study of the Huaihai Lymphoma Working Group.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) is a clinically rare subtype of DLBCL with aggressive clinical manifestations and a poor prognosis. It has been demonstrated that the prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is a significant prognostic factor for several types of lymphoma. The objective of this multicenter retrospective study was to explore the prognostic value of the PNI in patients with CD5-positive DLBCL. METHODS: In total, 207 patients with CD5-positive DLBCL were recruited from 11 centers of the Huaihai Lymphoma Working Group. Maximally selected rank statistics analysis was used to identify optimal cutoff points for the PNI. A Cox proportional hazards model was used for univariable and multivariable analyses. Kaplan-Meier curves were used to calculate survival rates and draw survival curves, and the log-rank test was used to compare differences between groups. RESULTS: The median age at diagnosis was 61 years, and the 5-year overall survival rate was 47.5%. According to the maximally selected rank statistics analysis, a score of 49.7 was the optimal cutoff point for the PNI. Subgroup analysis showed that the PNI could re-stratify patients in BCL-2-negative, MYC-negative, high-intermediate-risk and high-risk International Prognostic Index, BCL-6-positive and BCL-6-negative, high Ki-67 score (≥0.9), Ann Arbor stage III/IV, Eastern Cooperative Oncology Group performance status ≥2, and germinal center B subgroups. Multivariable analysis revealed that PNI, age, Eastern Cooperative Oncology Group performance status, albumin level, and red blood cell count were independent prognostic factors for CD5-positive DLBCL. CONCLUSIONS: The PNI was a significant prognostic indicator for CD5-positive DLBCL and was able to re-stratify the prognosis for clinicopathologic subgroups of patients with CD5-positive DLBCL.

Aerobic Copper-Catalyzed Intramolecular Cascade Oxidative Isomerization/[4+4] Cyclization of 2,2'-Disubstituted Stilbenes.

An aerobic copper-catalyzed cascade oxidative isomerization/[4+4] cyclization of 2,2'-disubstituted stilbenes is described. Under the mild CuCl/DBED/air catalytic system, various 5,10-heteroatom-containing tetrahydroindeno[2,1-a]indenes were efficiently prepared through the difunctionalizations of alkenes in a highly atom economic manner. Mechanistic investigations suggested the bicyclic product was likely formed through a sequence of rapid single-electron oxidation/[4+4] cyclization from 2,2'-disubstituted stilbene. The antarafacial manner of the thermally allowed [4+4] cyclization was further proven by series of control experiments and density functional theory calculations. Our findings provide an important addition to the aerobic copper-catalyzed oxidative cyclization.

New Cytotoxic Cycloartane Triterpenes from the Aerial Parts of Actaea heracleifolia (syn. Cimicifuga heracleifolia).

One new 15,16-seco-cycloartane triterpene (1: ), three new cycloartane triterpene glycosides (2: -4: ), and five known compounds (5: -9: ) were isolated from the aerial parts of Actaea heracleifolia. The chemical structures of these compounds were determined on the basis of NMR analysis, HRTOF-ESIMS data, and other spectroscopic methods. Selected compounds were evaluated for their cytotoxicity against human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) in vitro. Compounds 3: and 4: showed weak activity against the HL-60, A-549, and MCF-7 cell lines with IC50 values ranging from 21.34 to 36.98 µM.

A new indole alkaloid from Cimicifuga heracleifolia.

A new alkaloid, (E)-3-(3-methyl-1-oxo-2-butenyl)-6-methoxy-1 H -indole (1), along with two known ones, was isolated from the aerial parts of Cimicifuga heracleifolia. The structure of 1 was elucidated on the basis of extensive spectroscopic data analysis. The structures of known compounds were determined by comparison with the literature data.

Cimitriteromone A-G, Macromolecular Triterpenoid-Chromone Hybrids from the Rhizomes of Cimicifuga foetida.

Seven unprecedented high molecular weight hybrids of cycloartane triterpenoid saponins and chromone glycosides, namely, Cimitriteromone A-G (1-7), and three known biogenetic precursors (8-10) were isolated from the rhizomes of Cimicifuga foetida by using the HPLC-UV/MS method. The structures of the new compounds were determined by NMR analysis and HRESIMS data. The absolute configurations of sugar moieties were established by a chemical method. The new compounds 2 and 4 showed antiproliferative activities against Taxol-resistant human lung cancer A-549/Taxol with IC50 values of 15.73 ± 0.59 and 24.21 ± 0.61 µM, respectively, while the positive control groups cisplatin and Taxol gave IC50 values of 25.80 ± 1.15 and 0.60 ± 0.09 µM. Notably, compound 4 showed comparable cytotoxicity to the positive control, cisplatin, whereas the corresponding biogenetic precursors compounds 8 and 10 were inactive (IC50 > 40 µM).

Construction of tetracyclic 3-spirooxindole through cross-dehydrogenation of pyridinium: applications in facile synthesis of (±)-corynoxine and (±)-corynoxine B.

A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (±)-corynoxine and (±)-corynoxine B, were efficiently synthesized in five scalable steps.

Biomimetic Total Synthesis of Bimagnolignan: A Natural Anti-Breast Cancer Agent.

A short scalable biomimetic route to bioactive natural product bimagnolignan (1) was accomplished. Compound 1 was successfully prepared through a three-step metal-free synthesis from honokiol (2). Alternatively, 1 was also synthesized by biomimetic transformations that mimic tyrosinase in four steps. The key reactions feature a regioselective acetylation, a highly efficient C(sp2)-H oxidation, a cascade aerobic oxidative cyclization/coupling, and a Cu-catalyzed direct oxidative coupling. In addition, cell-based assays validate that 1 is a promising natural lead for HER2-positive breast cancer treatment.

Hydroxymethylation hydroxylation of 1,3-diarylpropene through a catalytic diastereoselective Prins reaction: cyclization logic and access to brazilin core.

A catalytic diastereoselective Prins reaction for hydroxymethylation and hydroxylation of 1,3-diarylpropene was successfully utilized to prepare various 1,3-dioxanes 7 in 14-88% yields. Take advantage of the synthetic intermediate 7h, the key B/C rings in brazilin core could be constructed by the sequential of Friedel-Crafts/Ullmann-Ma rather than Ullmann-Ma/Friedel-Crafts reactions.

Qualitative analysis on the transdermal absorption from the dichloromethane extract of the Sambucus adnata wall. based on UPLC-Q-Exactive Orbitrap/MS.

Sambucus adnata Wall.(SAW) has been used to treat osteoarthritis by the Yi nationality in China. The present study established an overall identification strategy based on ultra-high performance liquid chromatography-tandem Q-Exactive Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap/MS) method to characterize the multiple chemical constituents of SAW before and after percutaneous penetration. Nineteen compounds, including triterpenoids, fatty acids, lignans, flavonoid, and amide, were tentatively identified in the dichloromethane extract of SAW, while fourteen ingredients penetrated the skin. Among them, eleven components were reported for the first time in SAW.

A silicon-containing aryl/penta-1,4-dien-3-one/amine hybrid exhibits antiproliferative effects on breast cancer cells by targeting the HSP90 C-terminus without inducing heat-shock response.

A pharmacophore-hybridized strategy based on previously reported HSP90 C-terminal inhibitors was utilized to prepare 32 aryl/penta-1,4-dien-3-one/amine hybrids. Among them, a silicon-containing compound 1z exhibited remarkable broad-spectrum antiproliferative effects on various human breast cancer cell lines. Through fluorescence polarization and AlphaScreen-based assays, we demonstrated that 1z specifically inhibited the HSP90 C-terminus without affecting HSP90 N-terminus. Furthermore, 1z effectively inhibited the HSP90 C-terminus without inducing heat-shock response (HSR), leading to the degradation of its client proteins HER2, pAKT, AKT, and CDK4, causing G1 arrest of MCF-7 and SKBr3 cells, and ultimately contributing to apoptosis of these cells through caspase-3, caspase-8, and caspase-9 activation. Additionally, the penta-1,4-dien-3-one linker in the hybrid, a large bulky lipophilic substitution in the aryl fragment at the 3'-site, and the presence of N-methylpiperazine as the amine fragment were identified as crucial factors that significantly contributed to the observed antiproliferative activity through structure-activity relationship (SAR) analysis. Lastly, we found that 1z exhibited superior thermostability compared to vibsanin B derivatives and good in vitro metabolic stability in simulated intestinal fluid, representing one of the few reported silicon-containing HSP90 C-terminal inhibitors.

Risk factors for Encapsulating Peritoneal Sclerosis in patients undergoing peritoneal dialysis: A meta-analysis.

PURPOSE: Encapsulating Peritoneal Sclerosis (EPS) is the most serious complication of long-term peritoneal dialysis (PD), which considerably reduces the patient's quality of life, leading to patients discontinuing PD. Considering these negative effects, it is necessary to systematically review and determine the risk factors of EPS. METHODS: The PubMed, Embase, Web of Science, Cochrane Library, and China Biology Medicine (CBM) were searched from their inception to January 1st, 2022, and the bibliographies from the citations of relevant articles were manually searched. The ROBINS-I (Risk of Bias in Non-randomized studies of Interventions) tool was used to evaluate the risk of bias of included studies. RESULTS: Ten studies involving 12595 participants were included in this meta-analysis. The results revealed that a younger age at PD onset (MD = -7.70, 95% CI, -11.53~-3.86), a higher transporter (MD = 0.13, 95% CI, 0.09~0.18), a longer PD duration (SMD = 1.15, 95% CI, 0.68~1.61), a longer peritonitis duration (MD = 12.66, 95% CI, 3.85~21.47), and history of glomerulonephritis (OR = 1.42, 95% CI, 1.02~1.97) were significant risk factors for EPS. However, sex, use of icodextrin, the number of peritonitis episodes, and history of multicystic kidney disease did not affect the risk of EPS. CONCLUSIONS: This review provides a scientific basis for further understanding the etiology of PD-related EPS and improving prevention strategies. More high-quality studies are necessary to validate this paper's findings.

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 106/kg and 107/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 107/kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3-50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

α-C(sp3)-H Arylation of Cyclic Carbonyl Compounds.

α-C(sp3)-H arylation is an important type of C-H functionalization. Various biologically significant natural products, chemical intermediates, and drugs have been effectively prepared via C-H functionalization. Cyclic carbonyl compounds comprise of cyclic ketones, enones, lactones, and lactams. The α-C(sp3)-H arylation of these compounds have been exhibited high efficiency in forming C(sp3)-C(sp2) bonds, played a crucial role in organic synthesis, and attracted majority of interests from organic and medicinal communities. This review focused on the most significant advances including methods, mechanism, and applications in total synthesis of natural products in the field of α-C(sp3)-H arylations of cyclic carbonyl compounds in recent years.