Transformation of Renieramycin M into Renieramycins T and S by Intramolecular Photoredox Reaction of 7-Methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-5,8-dione Derivatives.

In connection with our studies of biologically active 1,2,3,4-tetrahydroisoquinoline marine natural products, we describe herein a useful intramolecular photoredox transformation of 7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-5,8-dione tricyclic models into 5-hydroxy-tetrahydroisoquinol[1,3]dioxoles in excellent yields. We applied this methodology to the transformation of renieramycin M into renieramycins T and S and the transformation of saframycin A. The results of cytotoxicity studies are also presented.

Light-Mediated Transformation of Renieramycins and Semisynthesis of 4'-Pyridinecarbonyl-Substituted Renieramycin-Type Derivatives as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells.

The semisynthesis of renieramycin-type derivatives was achieved under mild and facile conditions by attaching a 1,3-dioxole-bridged phenolic moiety onto ring A of the renieramycin structure and adding a 4'-pyridinecarbonyl ester substituent at its C-5 or C-22 position. These were accomplished through a light-induced intramolecular photoredox reaction using blue light (4 W) and Steglich esterification, respectively. Renieramycin M (4), a bis-tetrahydroisoquinolinequinone compound isolated from the Thai blue sponge (Xestospongia sp.), served as the starting material. The cytotoxicity of the 10 natural and semisynthesized renieramycins against non-small-cell lung cancer (NSCLC) cell lines was evaluated. The 5-O-(4'-pyridinecarbonyl) renieramycin T (11) compound exhibited high cytotoxicity with half-maximal inhibitory concentration (IC50) values of 35.27 ± 1.09 and 34.77 ± 2.19 nM against H290 and H460 cells, respectively. Notably, the potency of compound 11 was 2-fold more than that of renieramycin T (7) and equal to those of 4 and doxorubicin. Interestingly, the renieramycin-type derivatives with a hydroxyl group at C-5 and C-22 exhibited weak cytotoxicity. In silico molecular docking and dynamics studies confirmed that the mitogen-activated proteins, kinase 1 and 3 (MAPK1 and MAPK3), are suitable targets for 11. Thus, the structure-cytotoxicity study of renieramycins was extended to facilitate the development of potential anticancer agents for NSCLC cells.

N,N'-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3ß/c-Myc Signaling Pathway.

Lung cancer is one of the most common malignancies worldwide. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, shows chemotherapy resistance, metastasis, and relapse. The phosphatidylinositol-3 kinase (PI3K)/Akt pathway has been implicated in the carcinogenesis and disease progression of NSCLC, suggesting that it may be a promising therapeutic target for cancer therapy. Although phenylurea derivatives have been reported as potent multiple kinase inhibitors, novel unsymmetrical N,N'-diarylurea derivatives targeting the PI3K/Akt pathway in NSCLC cells remain unknown. METHODS: N,N'-substituted phenylurea derivatives CTPPU and CT-(4-OH)-PU were investigated for their anticancer proliferative activity against three NSCLC cell lines (H460, A549, and H292) by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, colony formation, Hoechst33342/PI staining assays, and apoptosis analysis. The protein expressions of Akt pathway-related proteins in response to CTPPU or CT-(4-OH)-PU were detected by Western blot analysis. The Kyoto Encyclopedia of Genes and Genomes mapper was used to identify the possible signaling pathways in NSCLC treated with CTPPU. The cell cycle was analyzed by flow cytometry. Molecular docking was used to investigate the possible binding interaction of CTPPU with Akt, the mammalian target of rapamycin complex 2 (mTORC2), and PI3Ks. Immunofluorescence and Western blot analysis were used to validate our prediction. RESULTS: The cytotoxicity of CTPPU was two-fold higher than that of CT-(4-OH)-PU for all NSCLC cell lines. Similarly, the non-cytotoxic concentration of CTPPU (25 µM) dramatically inhibited the colony formation of NSCLC cells, whereas its relative analog CT-(4-OH)-PU had no effect. Protein analysis revealed that Akt and its downstream effectors, namely, phosphorylated glycogen synthase kinase (GSK)-3ß (Ser9), ß-catenin, and c-Myc, were reduced in response to CTPPU treatment, which suggested the targeting of Akt-dependent pathway, whereas CT-(4-OH)-PU had no effect on such cell growth regulatory signals. CTPPU induced G1/S cell cycle arrest in lung cancer cells. Immunofluorescence revealed that CTPPU decreased p-Akt and total Akt protein levels, which implied the effect of the compound on protein activity and stability. Next, we utilized in silico molecular docking analysis to reveal the potential molecular targets of CTPPU, and the results showed that the compound could specifically bind to the allosteric pocket of Akt and three sites of mTORC2 (catalytic site, A-site, and I-site), with a binding affinity greater than that of reference compounds. The compound cannot bind to PI3K, an upstream regulator of the Akt pathway. The effect of CTPPU on PI3K and Akt was confirmed. This finding indicated that the compound could decrease p-Akt but caused no effect on p-PI3K. CONCLUSIONS: The results indicate that CTPPU significantly inhibits NSCLC cell proliferation by inducing G1/S cell cycle arrest via the Akt/GSK-3ß/c-Myc signaling pathway. Molecular docking revealed that CTPPU could interact with Akt and mTORC2 molecules with a high binding affinity. These data indicate that CTPPU is a potential novel alternative therapeutic approach for NSCLC.

In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones.

Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 µM) and HEL (IC50 = 3.31 and 6.65 µM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.

N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents.

New N-containing xanthone analogs of α-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, α-mangostin (1) was subsequently transformed in three steps to provide ether 2, amide 3, and amine 4 in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs 2-4 was described. Amine 4 showed promising cytotoxicity against the non-small-cell lung cancer H460 cell line fourfold more potent than that of cisplatin. Both compounds 3 and 4 possessed antitrypanosomal properties against Trypanosoma brucei rhodesiense at a potency threefold stronger than that of α-mangostin. Furthermore, ether 2 gave potent SARS-CoV-2 main protease inhibition by suppressing 3-chymotrypsinlike protease (3CLpro) activity approximately threefold better than that of 1. Fragment molecular orbital method (FMO-RIMP2/PCM) indicated the improved binding interaction of 2 in the 3CLpro active site regarding an additional ether moiety. Thus, the series of N-containing α-mangostin analogs prospectively enhance druglike properties based on isosteric replacement and would be further studied as potential biotically active chemical entries, particularly for anti-lung-cancer, antitrypanosomal, and anti-SARS-CoV-2 main protease applications.

5-O-(N-Boc-l-Alanine)-Renieramycin T Induces Cancer Stem Cell Apoptosis via Targeting Akt Signaling.

Cancer stem cells (CSCs) drive aggressiveness and metastasis by utilizing stem cell-related signals. In this study, 5-O-(N-Boc-l-alanine)-renieramycin T (OBA-RT) was demonstrated to suppress CSC signals and induce apoptosis. OBA-RT exerted cytotoxic effects with a half-maximal inhibitory concentration of approximately 7 µM and mediated apoptosis as detected by annexin V/propidium iodide using flow cytometry and nuclear staining assays. Mechanistically, OBA-RT exerted dual roles, activating p53-dependent apoptosis and concomitantly suppressing CSC signals. A p53-dependent pathway was indicated by the induction of p53 and the depletion of anti-apoptotic Myeloid leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins. Cleaved poly (ADP-ribose) polymerase (Cleaved-PARP) was detected in OBA-RT-treated cells. Interestingly, OBA-RT exerted strong CSC-suppressing activity, reducing the ability to form tumor spheroids. In addition, OBA-RT could induce apoptosis in CSC-rich populations and tumor spheroid collapse. CSC markers, including prominin-1 (CD133), Octamer-binding transcription factor 4 (Oct4), and Nanog Homeobox (Nanog), were notably decreased after OBA-RT treatment. Upstream CSCs regulating active Akt and c-Myc were significantly decreased; indicating that Akt may be a potential target of action. Computational molecular modeling revealed a high-affinity interaction between OBA-RT and an Akt molecule. This study has revealed a novel CSC inhibitory effect of OBA-RT via Akt inhibition, which may improve cancer therapy.

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis.

A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4'py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4'py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4'py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4'py)-JA. In vitro anticancer activity showed that 22-(4'py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4'py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4'py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

Semi-Synthesis of N-Aryl Amide Analogs of Piperine from Piper nigrum and Evaluation of Their Antitrypanosomal, Antimalarial, and Anti-SARS-CoV-2 Main Protease Activities.

Piper nigrum, or black pepper, produces piperine, an alkaloid that has diverse pharmacological activities. In this study, N-aryl amide piperine analogs were prepared by semi-synthesis involving the saponification of piperine (1) to yield piperic acid (2) followed by esterification to obtain compounds 3, 4, and 5. The compounds were examined for their antitrypanosomal, antimalarial, and anti-SARS-CoV-2 main protease activities. The new 2,5-dimethoxy-substituted phenyl piperamide 5 exhibited the most robust biological activities with no cytotoxicity against mammalian cell lines, Vero and Vero E6, as compared to the other compounds in this series. Its half-maximal inhibitory concentration (IC50) for antitrypanosomal activity against Trypanosoma brucei rhodesiense was 15.46 ± 3.09 µM, and its antimalarial activity against the 3D7 strain of Plasmodium falciparum was 24.55 ± 1.91 µM, which were fourfold and fivefold more potent, respectively, than the activities of piperine. Interestingly, compound 5 inhibited the activity of 3C-like main protease (3CLPro) toward anti-SARS-CoV-2 activity at the IC50 of 106.9 ± 1.2 µM, which was threefold more potent than the activity of rutin. Docking and molecular dynamic simulation indicated that the potential binding of 5 in the 3CLpro active site had the improved binding interaction and stability. Therefore, new aryl amide analogs of piperine 5 should be investigated further as a promising anti-infective agent against human African trypanosomiasis, malaria, and COVID-19.

Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells.

It has been recognized that cancer stem-like cells (CSCs) in tumor tissue crucially contribute to therapeutic failure, resulting in a high mortality rate in lung cancer patients. Due to their stem-like features of self-renewal and tumor formation, CSCs can lead to drug resistance and tumor recurrence. Herein, the suppressive effect of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from Thai blue sponge Xestospongia sp., on cancer spheroid initiation and self-renewal in the CSCs of human lung cancer cells is revealed. The depletion of stemness transcription factors, including Nanog, Oct-4, and Sox2 in the lung CSC-enriched population treated with jorunnamycin A (0.5 µM), resulted from the activation of GSK-3ß and the consequent downregulation of ß-catenin. Interestingly, pretreatment with jorunnamycin A at 0.5 µM for 24 h considerably sensitized lung CSCs to cisplatin-induced apoptosis, as evidenced by upregulated p53 and decreased Bcl-2 in jorunnamycin A-pretreated CSC-enriched spheroids. Moreover, the combination treatment of jorunnamycin A (0.5 µM) and cisplatin (25 µM) also diminished CD133-overexpresssing cells presented in CSC-enriched spheroids. Thus, evidence on the regulatory functions of jorunnamycin A may facilitate the development of this marine-derived compound as a novel chemotherapy agent that targets CSCs in lung cancer treatment.

Chemistry of Renieramycins. Part 19: Semi-Syntheses of 22-O-Amino Ester and Hydroquinone 5-O-Amino Ester Derivatives of Renieramycin M and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cell Lines.

Two new series of synthetic renieramycins including 22-O-amino ester and hydroquinone 5-O-amino ester derivatives of renieramycin M were semi-synthesized and evaluated for their cytotoxicity against the metastatic non-small-cell lung cancer H292 and H460 cell lines. Interestingly, the series of 22-O-amino ester derivatives displayed a potent cytotoxic activity greater than the hydroquinone derivatives. The most cytotoxic derivative of the series was the 22-O-(N-Boc-l-glycine) ester of renieramycin M (5a: IC50 3.56 nM), which showed 7-fold higher potency than renieramycin M (IC50 24.56 nM) and 61-fold more than jorunnamycin A (IC50 217.43 nM) against H292 cells. In addition, 5a exhibited a significantly higher cytotoxic activity than doxorubicin (ca. 100 times). The new semi-synthetic renieramycin derivatives will be further studied and developed as potential cytotoxic agents for non-small-cell lung cancer treatment.

Jorunnamycin A from Xestospongia sp. Suppresses Epithelial to Mesenchymal Transition and Sensitizes Anoikis in Human Lung Cancer Cells.

Metastasis is a key driving force behind the high mortality rate associated with lung cancer. Herein, we report the first study revealing the antimetastasis activity of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from a Thai blue sponge Xestospongia sp. evidenced by its inhibition of epithelial to mesenchymal transition (EMT), sensitization of anoikis, and suppression of anchorage-independent survival in human lung cancer cells. Treatment with jorunnamycin A (0.05-0.5 µM) altered the expression of p53 and Bcl-2 family proteins, particularly causing the down-regulation of antiapoptosis Bcl-2 and Mcl-1 proteins. Under detachment conditions for 12 h, jorunnamycin A-treated cells exhibited diminution of pro-survival proteins p-Akt and p-Erk as well as the survival-promoting factor caveolin-1. Corresponding with the inhibition on the Akt and Erk pathway as well as activation of p53, there was an increase in the epithelial marker E-cadherin and a remarkable decrease of EMT markers and associated proteins including vimentin, snail, and claudin-1. As the loss of anchorage dependence is an important barrier to metastasis, the observed inhibitory effects of jorunnamycin A on the coordinating networks of EMT and anchorage-independent growth emphasize the potential development of jorunnamycin A as an effective agent against lung cancer metastasis.

Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action.

Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.

5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis.

Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.

Avicequinone B sensitizes anoikis in human lung cancer cells.

BACKGROUND: During metastasis, cancer cells require anokis resistant mechanism to survive until reach the distant secondary tissues. As anoikis sensitization may benefit for cancer therapy, this study demonstrated the potential of avicequinone B, a natural furanonaphthoquinone found in mangrove tree (Avicenniaceae) to sensitize anoikis in human lung cancer cells. METHODS: Anoikis inducing effect was investigated in human lung cancer H460, H292 and H23 cells that were cultured in ultra-low attachment plate with non-cytotoxic concentrations of avicequinone B. Viability of detached cells was evaluated by XTT assay at 0-24 h of incubation time. Soft agar assay was performed to investigate the inhibitory effect of avicequinone B on anchorage-independent growth. The alteration of anoikis regulating molecules including survival and apoptosis proteins were elucidated by western blot analysis. RESULTS: Avicequinone B at 4 µM significantly induced anoikis and inhibited proliferation under detachment condition in various human lung cancer cells. The reduction of anti-apoptotic proteins including anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) associating with the diminution of integrin/focal adhesion kinase (FAK)/Proto-oncogene tyrosine-protein kinase (Src) signals were detected in avicequinone B-treated cells. CONCLUSIONS: Avicequinone B sensitized anoikis in human lung cancer cells through down-regulation of anti-apoptosis proteins and integrin-mediated survival signaling.

Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5-O-Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells.

A series of hydroquinone 5-O-monoester analogues of renieramycin M were semisynthesized via bishydroquinonerenieramycin M (5) prepared from renieramycin M (1), a major cytotoxic bistetrahydroisoquinolinequinone alkaloid isolated from the Thai blue sponge Xestospongia sp. All 20 hydroquinone 5-O-monoester analogues possessed cytotoxicity with IC50 values in nanomolar concentrations against the H292 and H460 human non-small-cell lung cancer (NSCLC) cell lines. The improved cytotoxicity toward the NSCLC cell lines was observed from the 5-O-monoester analogues such as 5-O-acetyl ester 6a and 5-O-propanoyl ester 7e, which exhibited 8- and 10-fold increased cytotoxicity toward the H292 NSCLC cell line (IC50 3.0 and 2.3 nM, respectively), relative to 1 (IC50 24 nM). Thus, the hydroquinone 5-O-monoester analogues are a new generation of the renieramycins to be further developed as potential marine-derived drug candidates for lung cancer treatment.

Synthesis, Biological Evaluation and Molecular Docking of Avicequinone C Analogues as Potential Steroid 5α-Reductase Inhibitors.

Avicequinone C (5a), a furanonaphthoquinone isolated from the Thai mangrove Avicennia marina has been shown previously to have interesting steroid 5α-reductase type 1 inhibitory activity. In this study, a series of avicequinone C analogues containing furanonaphthoquinone with different degrees of saturation and substituents at the furan ring were synthesized. The resulting synthetic avicequinone C and analogues (5a-f) along with some related compounds including 2,5-dihydroxy-1,4-benzoquinone (6) and natural naphthoquinones such as lawsone (7a) and lapachol (7b) were evaluated for their in vitro cell viability and steroid 5α-reductase type 1 inhibitory activities using the cultured cell line of human keratinocytes (HaCaT). This cell-based bioassay was performed based on a direct detection of the enzymatic product dihydrotestosterone (2) by using a non-radioactive high performance thin layer chromatography (HPTLC) method. Among the furanonaphthoquinones in this series, 5e having a propionic substituent at furan ring possessed approximately 22-fold more potent than the original isolated compound 5a. However, the compounds without furan motif such as 6, 7a and b could not inhibit the activity of steroid 5α-reductase. Molecular docking results of the in silico three-dimensional steroid 5α-reductase type 1-reduced nicotinamide adenine dinucleotide phosphate (NADPH) binary complex was performed via AutoDock Vina and it illustrated that the furanonaphthoquinone moiety and the substituent at furan ring might play a key role as pharmacophores for the steroid 5α-reductase inhibitory activity.

Chemistry of Renieramycins. 15. Synthesis of 22-O-Ester Derivatives of Jorunnamycin A and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cells.

Eighteen 22-O-ester derivatives of jorunnamycin A (2) were prepared via 2, and their cytotoxicity against human non-small-cell lung cancer (NSCLC) cells was evaluated. Preliminary study of the structure-cytotoxicity relationship revealed that the ester part containing a nitrogen-heterocyclic ring elevated the cytotoxicity of the 22-O-ester derivatives. Among them, 22-O-(4-pyridinecarbonyl) ester 6a is the most potent compound (IC50 1.1 and 1.6 nM), exhibiting 21-fold and 5-fold increases in cytotoxicity against the H292 and H460 NSCLC cell lines, respectively, relative to renieramycin M (1), the major cytotoxic bistetrahydroisoquinolinequinone alkaloid of the Thai blue sponge Xestospongia sp.

Synthesis and Absolute Configuration of Acanthodendrilline, a New Cytotoxic Bromotyrosine Alkaloid from the Thai Marine Sponge Acanthodendrilla sp.

Acanthodendrilline (1), a new bromotyrosine alkaloid, was isolated from the Thai marine sponge Acanthodendrilla sp. The structure of 1 was fully characterized by spectroscopic analysis, in agreement with the synthesized compound used to resolve the single chiral center at C-11. Total synthesis of the enantiomers of 1 allowed for the comparison of specific rotation values and hence the determination of the absolute configuration as 11-S. Cytotoxicity evaluation revealed that (S)-1 exhibited approximately three-fold more potent cytotoxicity against the human non-small cell lung cancer H292 cell line than (R)-1.

Synthesis of (±)-spongiolactone enabling discovery of a more potent derivative.

An eleven-step synthesis of (±)-spongiolactone from 1,3-cyclohexanedione is reported that relies on a diastereoselective, nucleophile-catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated ß-lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure-activity studies that revealed a regio- and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.

Inulin supplementation exhibits increased muscle mass via gut-muscle axis in children with obesity: double evidence from clinical and in vitro studies.

Gut microbiota manipulation may reverse metabolic abnormalities in obesity. Our previous studies demonstrated that inulin supplementation significantly promoted Bifidobacterium and fat-free mass in obese children. We aimed to study gut-muscle axis from inulin supplementation in these children. In clinical phase, the plasma samples from 46 participants aged 7-15 years, were analyzed for muscle biomarkers before and after 6-month inulin supplementation. In parallel, the plausible mechanism of muscle production via gut-muscle axis was examined using macrophage cell line. Bifidobacterium was cultured in semi-refined medium with inulin used in the clinical phase. Cell-free supernatant was collected and used in lipopolysaccharide (LPS)-induced macrophage cell line to determine inflammatory and anti-inflammatory gene expression. In clinical phase, IL-15 and creatinine/cystatin C ratio significantly increased from baseline to the 6th month. In vitro study showed that metabolites derived from Bifidobacterium capable of utilizing inulin contained the abundance of SCFAs. In the presence of LPS, treatment from Bifidobacterium + inulin downregulated TNF-α, IL-6, IL-1ß, and iNOS, but upregulated FIZZ-1 and TGF-ß expression. Inulin supplementation promoted the muscle biomarkers in agreement with fat-free mass gain, elucidating by Bifidobacterium metabolites derived from inulin digestion showed in vitro anti-inflammatory activity and decreased systemic pro-inflammation, thus promoting muscle production via gut-muscle axis response.Clinical Trial Registry number: NCT03968003.