A prospective single-arm study on the relationship between dose-volume parameters of pelvic functional bone marrow and acute hematological toxicities during intensity-modulated radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer.

BACKGROUND: FLT-PET/CT can accurately identify and locate functional bone marrow (FBM) with hematopoietic capability, the FBM were divided into two levels as FBM1 (strongest hemopoietic ability region)and FBM2 (moderate hemopoietic ability region) via FLT-PET/CT. The purpose of this study was to explore the relationship between dose-volume parameters of pelvic FBM and hematologic toxicity (HT) during radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer. METHODS: From December 2016 to September 2021, ninety-seven uterine cervical/endometrial cancer patients received intensity-modulated radiation therapy were prospectively recruited in this single-arm, prospective, phase II trial. Blood counts were reviewed weekly during radiotherapy. Single- and multifactor regression methods were used to analyze the relationships between dose-volume parameters of FBM1/2 and grade ≥ 2 HT. ROC curves were used to determine the cutoff values for the dose-volume parameters of FBM1/2. RESULTS: The incidence of grade ≥ 2 leukopenia, neutropenia, thrombocytopenia and anemia in patients during radiotherapy was 63.9%, 45.4%, 19.6% and 38.8% respectively, and the median occurrence time was the 29th, 42th, 35th and 31th day, respectively. Multivariate regression analysis showed that the Dmax of FBM1 was significantly related to grade ≥ 2 leukopenia (OR = 1.277 95% CI 1.067-1.528, P = 0.008), Dmean of FBM2 was significantly related to grade ≥ 2 thrombocytopenia (OR = 1.262 95% CI 1.066-1.494, P = 0.007), and V10 of FBM1 was significantly related to grade ≥ 2 anemia (OR = 1.198 95% CI 1.003-1.431, P = 0.046). The incidence of grade ≥ 2 leukopenia for patients with FBM1 Dmax < 53 Gy was lower than that for patients with FBM1 Dmax ≥ 53 Gy (53.4% vs. 95.8%, P < 0.001). The incidence of grade ≥ 2 thrombocytopenia in patients with FBM2 Dmean < 33 Gy was lower than that in patients with FBM2 Dmean ≥ 33 Gy (0 vs. 28.4%, P < 0.001). The incidence of grade ≥ 2 anemia for patients with FBM1 V10 < 95% was lower than that in patients with FBM1 V10 ≥ 95% (24.4% vs. 57.1%, P = 0.003). CONCLUSIONS: Grade ≥ 2 HT usually occurs in the 4th week of radiotherapy for patients with uterine cervical/endometrial cancer. The Dmax and V10 of FBM1 and the Dmean of FBM2 were significantly associated with the occurrence of grade ≥ 2 HT. The recommended optimal dose constraints were FBM1 Dmax < 53 Gy, V10 < 95%, and FBM2 Dmean <33 Gy.

Investigating Doxorubicin's mechanism of action in cervical cancer: a convergence of transcriptomic and metabolomic perspectives.

Introduction: Cervical cancer remains a significant global health burden, and Doxorubicin is a crucial therapeutic agent against this disease. However, the precise molecular mechanisms responsible for its therapeutic effects are not fully understood. Methods: In this study, we employed a multi-omics approach that combined transcriptomic and metabolomic analyses with cellular and in vivo experiments. The goal was to comprehensively investigate the molecular landscape associated with Doxorubicin treatment in cervical cancer. Results: Our unbiased differential gene expression analysis revealed distinct alterations in gene expression patterns following Doxorubicin treatment. Notably, the ANKRD18B gene exhibited a prominent role in the response to Doxorubicin. Simultaneously, our metabolomic analysis demonstrated significant perturbations in metabolite profiles, with a particular focus on L-Ornithine. The correlation between ANKRD18B gene expression and L-Ornithine levels indicated a tightly controlled gene-metabolite network. These results were further confirmed through rigorous cellular and in vivo experiments, which showed reductions in subcutaneous tumor size and significant changes in ANKRD18B, L-Ornithine, and Doxorubicin concentration. Discussion: The findings of this study underscore the intricate interplay between transcriptomic and metabolomic changes in response to Doxorubicin treatment. These insights could have implications for the development of more effective therapeutic strategies for cervical cancer. The identification of ANKRD18B and L-Ornithine as key components in this process lays the groundwork for future research aiming to unravel the complex molecular networks that underlie Doxorubicin's therapeutic mechanism. While this study provides a solid foundation, it also highlights the necessity for further investigation to fully grasp these interactions and their potential implications for cervical cancer treatment.

The Anti-Tumor Mechanism and Target of Triptolide Based on Network Pharmacology and Molecular Docking.

BACKGROUND: According to the special physiological and pharmacological activities of natural compounds, many drugs with special therapeutic effects have been developed. The Triptolide (TP) is a natural anti-tumor drug with a world patent, but its target and mechanism are yet unknown. OBJECTIVE: The study aims to explore and predict the target and mechanism of TP on Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer (PC) and Colorectal Cancer (CC) through network pharmacology technology. METHODS: We screened the core targets of TP with NSCLC, PC and CC, respectively, and carried out network analysis, enrichment analysis and ligand-receptor docking to clarify its potential pharmacological mechanism. RESULTS: By screening the core genes between TP with NSCLC, PC and CC, respectively, it was found that PTGS2 was the common target gene in the three cancers. NSCLC, CCL2, IL6, HMOX1 and COL1A1 are the specific target genes, while MMP2, JUN, and CXCL8 are the specific target genes in PC. In CC, the specific target genes includeERBB2, VEGFA, STAT1 and MAPK8. In enrichment analysis, it was found that the NF- κB, toll-like receptors and IL-17 signaling pathway were mainly involved in TP for these cancers. The binding energy of TP to the core target is less than that of cyclophosphamide. CONCLUSION: This study preliminarily revealed that TP may prevent and treat cancers\ through multiple targets and pathways. The possible mechanisms of TP include regulating immune and inflammatory responses, promoting apoptosis and inhibiting tumor development. It shows that TP may have potential in treating kinds of tumors.

Rhodium(III)-Catalyzed Direct Coupling of Quinoline-8-Carbaldehydes with (Het)Arylboronic Acids for the Synthesis of 8-Aryloylquinolines.

Herein, we describe a method for the synthesis of aryl-(het)aryl ketones by Rh(III)-catalyzed direct coupling between quinoline-8-carbaldehydes and (het)arylboronic acids. The method has a broad substrate scope, a high functional group tolerance, and uses commercially available starting materials. Scale-up of the reaction and subsequent synthesis of tubulin polymerization inhibitor demonstrated its utilities. A plausible mechanism was proposed on the basis of the fact that a stable cycloacylrhodium intermediate complex could be used as catalyst, and the complex reacted stoichiometrically with (het)arylboronic acids.

Design, Synthesis, and Biological Activity of ß-Carboline Analogues Containing Hydantoin, Thiohydantoin, and Urea Moieties.

A series of novel ß-carboline derivatives was designed by combining the anti-tobacco mosaic virus (TMV) lead compound tetrahydro-ß-carboline ester with the hydantoin, thiohydantoin, and urea motifs. These derivatives were synthesized from tetrahydro-ß-carboline ester via a structural diversity-oriented synthesis in one step, and their biological activities were evaluated. Most of the derivatives exhibited anti-TMV activity higher than that of commercial plant virucide ribavirin, such as compounds 2, 4, 5, 7, 9, 15, 16, 19, and 21. Compared with the lead compounds, some of these derivatives showed good insecticidal activity against Plutella xylostella and Culex pipiens pallens. At the same time, these derivatives also showed broad-spectrum fungicidal activity. The systematic study provides strong evidence that the hydantoin, thiohydantoin, and urea motifs of these molecules can improve and modulate the activities of the analogues of natural products.

Silver-copper co-catalyzed cascade intramolecular cyclization/desulfinamide/dehydrogenation: one-pot synthesis of substituted carbazoles.

Herein, a silver and copper co-catalyzed cascade intramolecular cyclization/desulfinamide/dehydrogenation reaction for the synthesis of substituted carbazoles is reported. This reaction, which involved formation of new C-C and C-N bonds as well as C-N bond cleavage, afforded diverse carbazoles in high yields and showed good functional group tolerance.

Dehydrogenation of N-Heterocycles by Superoxide Ion Generated through Single-Electron Transfer.

Nitrogen-containing heteroarene motifs are found in numerous pharmaceuticals, natural products, and synthetic materials. Although several elegant methods for synthesis of these compounds through dehydrogenation of the corresponding saturated heterocycles have been reported, some of the methods are hampered by long reaction times, harsh conditions, and the need for catalysts that are not readily available. This work reports a novel method for dehydrogenation of N-heterocycles. Specifically, O2.- generated in situ acts as the oxidant for N-heterocycle substrates that are susceptible to oxidation through a hydrogen atom transfer mechanism. This method provides a general, green route to N-heteroarenes.

Copper-Catalyzed Aerobic Oxidative [2 + 3] Cyclization/Aromatization Cascade Reaction: Atom-Economical Access to Tetrasubstituted 4,5-Biscarbonyl Imidazoles.

An atom-economical method for accessing tetrasubstituted 4,5-biscarbonylimidazoles by reaction between glycine derivatives and 5-alkoxyoxazoles is reported. The method, which involves a copper-catalyzed aerobic oxidative [2 + 3] cyclization/aromatization cascade process, starts from readily available and inexpensive materials, uses molecular oxygen as a co-oxidant, and has a broad substrate scope.

Skeletal modifications of ß-carboline alkaloids and their antiviral activity profile.

To study the effect of the variation of fused ring size and substitution on the antiviral activity of [Formula: see text]-carboline alkaloids, four types of structurally novel [Formula: see text]-carboline alkaloids analogues, with indole-fused six- to nine-membered-rings motifs, were designed, synthesized, and evaluated for the inhibition of tobacco mosaic virus (TMV). Bioassay results indicated that most of these analogues had significant anti-TMV activity; especially I-14 (54 [Formula: see text] 3 % at 500 [Formula: see text]g/mL in vitro; 51 [Formula: see text] 2, 45 [Formula: see text] 2, and 42 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vivo), II-4 (53 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vitro; 49 [Formula: see text] 2, 57 [Formula: see text] 2, and 48 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vivo), and II-8 (48 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vitro; 53 [Formula: see text] 2 %, 56 [Formula: see text] 2 %, and 46 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vivo), which were more potent vs. TMV than was ribavirin (36 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vitro; 37 [Formula: see text] 2, 41 [Formula: see text] 2, and 38 [Formula: see text] 1 % at 500 [Formula: see text]g/mL in vivo). The size of the fused ring has important effects on anti-TMV potency, which may be ascribed to conformational differences. The X-ray structures of I-1, I-6, II-8, and III show differing conformational preferences. The most potent compounds can be used as leads for further optimization as antiphytoviral agents.

C ring may be dispensable for ß-carboline: Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of ß-carboline alkaloids.

According to our previous work and the latest research on the biosynthesis of ß-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of ß-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure-activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3±2.1%, 67.1±1.9%, 68.7±1.3%, and 64.5±3.1%, 500µg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.

Synthesis of Structurally Diverse 2,3-Fused Indoles via Microwave-Assisted AgSbF6-Catalysed Intramolecular Difunctionalization of o-Alkynylanilines.

2,3-Fused indoles are found in numerous natural products and drug molecules. Although several elegant methods for the synthesis of this structural motif have been reported, long reaction times and harsh conditions are sometimes required, and the yields tend to be low. Herein, we report a microwave method for straightforward access to various types of 2,3-fused indoles via AgSbF6-catalysed intramolecular difunctionalization of o-alkynylanilines. AgSbF6 played a role in both the hydroamination step and the imine-formation step. This method, which exhibited excellent chemoselectivity (no ring-fused 1,2-dihydroquinolines were formed), was used for formal syntheses of the natural products conolidine and ervaticine and the antihistamine drug latrepirdine.

Regio- and chemoselective N-1 acylation of indoles: Pd-catalyzed domino cyclization to afford 1,2-fused tricyclic indole scaffolds.

A concise method for the synthesis of 1,2-fused tricyclic indole scaffolds by domino cyclization involving a Pd-catalyzed Sonogashira coupling, indole cyclization, regio- and chemoselective N-1 acylation, and 1,4-Michael addition is reported. This method provides straightforward access to tetrahydro[1,4]diazepino[1,2-a]indole and hexahydro[1,5]diazocino[1,2-a]indole scaffolds.

Design, synthesis, anti-TMV, fungicidal, and insecticidal activity evaluation of 1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid derivatives based on virus inhibitors of plant sources.

By drawing the creation ideas of botanical pesticides, a series of tetrahydro-ß-carboline-3-carboxylic acid derivatives were designed and synthesized, and first evaluated for their anti-TMV, fungicidal and insecticidal activities. Most of these derivatives exhibited good antiviral activity against TMV both in vitro and in vivo. Especially, the activities of compounds 8 and 15 in vivo were higher than that of ribavirin. The compound 8 exhibited more than 70% fungicidal activities against Cercospora arachidicola Hori, Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50mg/kg, compounds 16 and 20 exhibited more than 60% insecticidal activities against Mythimna separate and Ostrinia nubilalis.

Design, synthesis, and antiviral, fungicidal, and insecticidal activities of tetrahydro-ß-carboline-3-carbohydrazide derivatives.

According to our previous research on the antiviral activity of ß-carboline and tetrahydro-ß-carboline derivatives, using (1S,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (1) as a lead compound, series of novel tetrahydro-ß-carboline derivatives containing acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. Most of these compounds exhibited excellent antiviral activity both in vitro and in vivo. The in vivo inactivation, curative, and protection activities of compounds 8, 9, 12, 16, 28, 29, and 30 were much higher than that of ribavirin (37.6%, 39.4%, and 37.9% at 500 µg/mL) and the lead compound (40.0%, 42.3%, and 39.6% at 500 µg/mL). Especially, the in vitro and in vivo activities of compound 16 (36.9%, 33.6%, 30.2%, and 35.8%) at 100 µg/mL, which were very close to that of ribavirin (40.0% for in vitro activity) at 500 µg/mL. Compounds 9 and 29 were chosen for the field trials of antiviral efficacy against TMV (tobacco mosaic virus); the results exhibited that both compounds, especially compound 29, showed better activities than control plant virus inhibitors. At the same time, the fungicidal results showed that compounds 6, 9, and 11 exhibited good fungicidal activities against 14 kinds of phytopathogens. Additionally, compounds 3 and 23 exhibited moderate insecticidal activity against the four tested species of insects.