Integrated multi-omics analyses reveal Jorunnamycin A as a novel suppressor for muscle-invasive bladder cancer by targeting FASN and TOP1.

BACKGROUND: Bladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied. METHODS: To examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed. RESULTS: JorA inhibited the proliferation of MIBC cells, and the IC50 of T24 and UM-UC-3 was 0.054 and 0.084 µM, respectively. JorA-induced significantly changed proteins were enriched in "cancer-related pathways" and "EGFR-related signaling pathways", which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were - 8.153 and - 7.264 kcal/mol, respectively). CONCLUSIONS: The marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.

Formal Synthesis of Ecteinascidin 743 from N-Cbz-l-tyrosine.

A formal total synthesis of ecteinascidin 743 and lurbinectedin is achieved. Key features involve a Pictet-Spengler cyclization coupling of the tetrahydroisoquinoline and phenylalaninol moieties prepared by a common route with high yield and selectivity, a Parikh-Doering oxidation with good chemoselectivity and functionality tolerance, and a light-mediated A-ring elaboration of pentacyclic methoxyquinone substrates. By the approach, the known advanced intermediate (4-step conversion to Et-743) can be obtained conveniently in 21 total steps from N-Cbz-l-tyrosine.

Comprehensive Review of Recent Advances in Chiral A-Ring Flavonoid Containing Compounds: Structure, Bioactivities, and Synthesis.

Flavonoids are a group of natural polyphenolic substances that are abundant in vegetables, fruits, grains, and tea. Chiral A-ring-containing flavonoids are an important group of natural flavonoid derivatives applicable in a wide range of biological activities such as, cytotoxic, anti-inflammatory, anti-microbial, antioxidant, and enzyme inhibition. The desirable development of chiral A-ring-containing flavonoids by isolation, semi-synthesis or total synthesis in a short duration proves their great value in medicinal chemistry research. In this review, the research progress of chiral A-ring-containing flavonoids, including isolation and extraction, structural identification, pharmacological activities, and synthetic methods, is comprehensively and systematically summarized. Furthermore, we provide suggestions for future research on the synthesis and biomedical applications of flavonoids.

Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy.

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2), are two of the most complicated transcription regulators, which participate in a variety of physiological processes. Numerous studies have shown that they are overactivated in multiple types of tumors. Interestingly, STAT3 and NRF2 can also interact with each other to regulate tumor progression. Hence, these two important transcription factors are considered key targets for developing a new class of antitumor drugs. This review summarizes the pivotal roles of the two transcription regulators and their interactions in the tumor microenvironment to identify potential antitumor drug targets and, ultimately, improve patients' health and survival.

Renieramycin T Inhibits Melanoma B16F10 Cell Metastasis and Invasion via Regulating Nrf2 and STAT3 Signaling Pathways.

As one of marine tetrahydroisoquinoline alkaloids, renieramycin T plays a significant role in inhibiting tumor metastasis and invasion. However, the effect of renieramycin T on inflammation-related tumor metastasis and invasion is still unknown, and its mechanisms remain unclear. Here we established an inflammation-related tumor model by using the supernatant of RAW264.7 cells to simulate B16F10 mouse melanoma cells. The results indicate that renieramycin T suppressed RAW264.7 cell supernatant-reduced B16F10 cell adhesion to a fibronectin-coated substrate, migration, and invasion through the matrigel in a concentration-dependent manner. Moreover, Western blot results reveal that renieramycin T attenuated the phosphorylation of STAT3 and down-regulated the expression of Nrf2. Together, the above findings suggest a model of renieramycin T in suppressing B16F10 cancer cell migration and invasion. It may serve as a promising drug for the treatment of cancer metastasis.

Single-Cell RNA Sequencing Reveals Heterogeneity of Myf5-Derived Cells and Altered Myogenic Fate in the Absence of SRSF2.

Splicing factor SRSF2 acts as a critical regulator for cell survival, however, it remains unknown whether SRSF2 is involved in myoblast proliferation and myogenesis. Here, knockdown of SRSF2 in myoblasts causes high rates of apoptosis and defective differentiation. Combined conditional knockout and lineage tracing approaches show that Myf5-cre mice lacking SRSF2 die immediately at birth and exhibit a complete absence of mature myofibers. Mutant Myf5-derived cells (tdtomato-positive cells) are randomly scattered in the myogenic and non-myogenic regions, indicating loss of the community effect required for skeletal muscle differentiation. Single-cell RNA-sequencing reveals high heterogeneity of myf5-derived cells and non-myogenic cells are significantly increased at the expense of skeletal muscle cells in the absence of SRSF2, reflecting altered cell fate. SRSF2 is demonstrated to regulate the entry of Myf5 cells into the myogenic program and ensures their survival by preventing precocious differentiation and apoptosis. In summary, SRSF2 functions as an essential regulator for Myf5-derived cells to respond correctly to positional cues and to adopt their myogenic fate.

Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.

NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.

Natural Phytochemicals in Bladder Cancer Prevention and Therapy.

Phytochemicals are natural small-molecule compounds derived from plants that have attracted attention for their anticancer activities. Some phytochemicals have been developed as first-line anticancer drugs, such as paclitaxel and vincristine. In addition, several phytochemicals show good tumor suppression functions in various cancer types. Bladder cancer is a malignant tumor of the urinary system. To date, few specific phytochemicals have been used for bladder cancer therapy, although many have been studied in bladder cancer cells and mouse models. Therefore, it is important to collate and summarize the available information on the role of phytochemicals in the prevention and treatment of bladder cancer. In this review, we summarize the effects of several phytochemicals including flavonoids, steroids, nitrogen compounds, and aromatic substances with anticancer properties and classify the mechanism of action of phytochemicals in bladder cancer. This review will contribute to facilitating the development of new anticancer drugs and strategies for the treatment of bladder cancer using phytochemicals.

Synthesis, characterization and theoretical investigation of a new chalcohalide, Ba4GaS4F3.

A new fluorine-containing chalcohalide, Ba4GaS4F3, has been synthesized by conventional high-temperature solid-state reaction. The compound crystallizes in the centrosymmetric space group I41/a with a = b = 16.628 (5) Å, c = 17.139 (10) Å, Z = 16. Experimental and theoretical results confirm that Ba4GaS4F3 is a direct band gap compound with an experimental band gap of about 3.13 eV, and the band gap is mainly determined by the Ba-5p, F-2p and S-3p orbitals. What's more, different from the many newly discovered chalcohalides in the Ba3AM4Q (A = Ga, In; M = S, Se; Q = Cl, Br, I) family, Ba4GaS4F3 is the first reported compound in the Ba4AM4D3 (A = Ga, In; M = chalcogen; D = halogen) family. The results enrich the structural diversity of metal chalcohalides.

The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target.

The orphan receptor APJ and its endogenous ligand apelin, which are expressed in the brain, are the major components of the apelin/APJ system. Growing evidence shows that the apelin/APJ system plays a vital role in the pathophysiology of cerebral ischemic injury. Targeting the apelin/APJ system may have protective effects on cerebral ischemic injury. In this review, we sum up the latest research progress relating to the actions and therapeutic potential of the apelin/APJ system in ischemic stroke. An in-depth knowledge of the pathophysiological effects of the apelin/APJ system and the underlying mechanisms will help to develop novel therapeutic interventions for ischemic stroke.

Sphingosine-1-phosphate signal transducer and activator of transcription 3 signaling pathway contributes to baicalein-mediated inhibition of dextran sulfate sodium-induced experimental colitis in mice.

BACKGROUND: Baicalein has been shown to have anti-inflammatory and anti-tumor activities. However, the mechanisms underlying its anti-inflammatory effect on colitis remain unclear. METHODS: A dextran sodium sulfate (DSS)-induced model of acute colitis was established in BALB/c mice (6-8 weeks old, weighing 18-22 g). Six groups of mice received: (1) water for 10 days (control), n = 6; (2) DSS 4% solution in the drinking water for 7 days, followed by normal water for 3 days, n = 7; (3), (4), and (5) as for group 2 plus baicalein (10, 20, 40 mg/kg) administered once daily starting on day 1, n = 6; and (6) as for (2) plus 5-aminosalicylic acid (50 mg/kg) administered once daily starting on day 1, n = 6. Body weights, stool consistency, and hematochezia were recorded, and the severity of colitis was evaluated using a disease activity index. On day 11, the mice were euthanized, and organs and blood were collected for analysis. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay; CD11b-positive cells were analyzed by immunofluorescence microscopy; expression of retinoic-acid-receptor-related orphan nuclear receptor gamma, sphingosine kinase 1 (SPHK1), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was detected by immunohistochemistry; and expression of nucleotide-binding oligomerization domain 2 (NOD2), SPHK1, sphingosine 1-phosphate receptor 1 (S1PR1), total STAT3, and p-STAT3 were detected by western blotting analysis. Inter-group differences were compared using Student's t test. RESULTS: Baicalein treatment dose-dependently reduced DSS-induced weight loss (P < 0.01 or P < 0.05), splenomegaly (P < 0.01), and colonic damage, as reflected by amelioration of diarrhea, rectal bleeding, and colonic ulceration, congestion, edema (shown as colon length, P < 0.05 or P < 0.01), and inflammatory cell infiltration. Baicalein also significantly decreased the levels of inflammatory mediators in the serum (P < 0.01) and colon, and significantly inhibited expression of NOD2 SPHK1, S1PR1, and p-STAT3 in the colon (P < 0.05). CONCLUSIONS: Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling, suggesting that this flavonoid might be beneficial in the treatment of colitis.

Convergent Formal Synthesis of Ecteinascidin 743.

A concise formal synthesis of ecteinascidin 743 is described. Key features involve the coupling of the multisubstituted tetrahydroisoquinoline and phenylalaninol moieties via a regio- and stereoselective Pictet-Spengler cyclization as well as the subsequent chemoselective MOM protection of the phenol group, which opens a rapid access to the desirable pentacycle. The synthesis successfully delivered the advanced intermediate with the characteristic macrolactone from sesamol in 23 steps.

Structural insights into T2-cluster-containing chalcogenides with vertex-, edge- and face-sharing connection modes of NaQ6 ligands: Na3ZnMIIIQ4 (MIII = In, Ga; Q = S, Se).

A series of quaternary chalcogenides, Na3ZnMIIIQ4 (MIII = In, Ga; Q = S, Se), were successfully synthesized for the first time through a high temperature solid-state reaction method. All of them exhibit similar structures and crystallize in the I41/acd space group of the tetragonal system. In their structures, typical super-tetrahedron (T2-type) clusters composed of four vertex-sharing (Zn/MIII)S4 tetrahedra are discovered and these T2-clusters further link together to form interesting wavelike chains. Adjacent T2 clusters present a torsion angle of 24.6° with each other when viewed along the c-axis, which has rarely been found among all the reported T2-containing chalcogenides. Moreover, we have systematically investigated the connection modes of NaSn (n = 4-6) in all the known Na-contained quaternary sulfides, and the result shows that the connection modes (corner-, edge-, and face-sharing) of NaS6 ligands in the title sulfides are also rarely (only 3%) found. Besides, the optical properties including diffuse-reflection and Raman spectra are systematically characterized. Theoretical calculations based on the first principles theory were also used to analyze their structure-performance relationships.

Asymmetric synthesis of (-)-renieramycin T.

(-)-Renieramycin T, an interesting tetrahydroisoquinolinequinone alkaloid with a novel renieramycin-ecteinascidin mixed framework, is synthesized from the known phenol 16 in 22 steps with 6.2% overall yield. In the convergent route, the key cyclocondensation between the isoquinoline moiety 27 and trisubstituted phenylalaninol 14 is achieved with good selectivity to furnish bistetrahydroisoquinoline 29, which permits a rapid construction of the pentacyclic framework having a fully substituted aromatic A ring.

Novel chemosensors for detection of glutathione by reduction or substitution of naphthalimide derivatives containing sulfoxide or sulfone substituents.

A series of compounds, naphthalimide derivatives containing sulfoxide or sulfone substituents, were easily synthesized and characterized, which can be used for detection of glutathione. The detailed spectral studies demonstrated that the compounds displayed high selectivity for glutathione over cysteine, homocysteine and other biological molecules. Further studies suggested that reduction or nucleophilic substitution of sulfoxide or sulfone substituents of naphthalimide compounds by thiols induced ICT process in the chemosensors, and then resulted in fluorescence intensity enhancement. Also, the compounds were proved to be useful for imaging GSH in living cells. The nucleophilic substitution mechanism further revealed that the compounds were potential reagents for labeling sulfhydryl protein.

A rapid and efficient access to renieramycin-type alkaloids featuring a temperature-dependent stereoselective cyclization.

A flexible and practical protocol for the asymmetric synthesis of renieramycin-type antitumor alkaloids is described, in which the stereoselective Pictet-Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (-)-Renieramycin G and (-)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from l-tyrosine with 15.8% and 14.3% overall yield respectively.

Asymmetric total synthesis of (-)-jorunnamycins A and C and (-)-jorumycin from L-tyrosine.

Three renieramycin-type antitumor alkaloids, (-)-jorunnamycins A (1) and C (2) and (-)-jorumycin (3), have been synthesized by a new convergent approach, which features a highly regio- and stereoselective Pictet-Spengler cyclization to couple the isoquinoline and the trisubstituted phenylalaninol partners. This synthetic strategy opens an economical access to these important antitumor alkaloids with high yields: (-)-jorunnamycin A, as a common precursor to other renieramycin-type alkaloids and their analogues, is obtained with 18.1% overall yield from l-tyrosine.

Catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine: access to asymmetric construction of several heterocycles.

Several novel heterocycles have been constructed asymmetrically on the basis of a catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine. The combination of phenylphosphilic acid and trifluoroethanol is exploited to promote an Ugi-type reaction with α-isocyanoacetamide for the first time. By means of this reaction, chiral 3-oxazolyl morpholin-2-one/piperazin-2-one derivatives are synthesized with high yields and excellent stereoselectivities. As electron-rich azadienes, these condensation products are further transformed to fused tricyclic frameworks by treatment with appropriate dienophiles such as maleic anhydride and unsaturated acyl chlorides via domino processes. Moreover, a one-pot, three-component synthesis of the chiral tricyclic frameworks from isocyanoacetamide, imine, and maleic anhydride is also feasible.

An asymmetric Ugi three-component reaction induced by chiral cyclic imines: synthesis of morpholin- or piperazine-keto-carboxamide derivatives.

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.