Progress on synthesis and structure-activity relationships of lamellarins over the past decade.

Lamellarins are polyaromatic alkaloids isolated from marine organisms, including mollusks, tunicates, and sponges. Currently, over 60 structurally distinct natural lamellarins have been reported, and most of them exhibit promising biological activities, such as topoisomerase inhibition, mitochondrial function inhibition, multidrug resistance reversing, and anti-HIV activity. There has also been a significant progress on the synthetic study of lamellarins which has been regularly updated by numerous medicinal chemists as well. This review provides a detailed summary of the synthesis, pharmacology, and structural modification of lamellarins over the past decades.

New bioactive secondary metabolites from the soil-derived Streptomyces sp. S045 and their anti-bacterial and anti-type III secretion system activities.

A total of seven compounds were isolated from the ISP3 agar cultures of a soil-derived Streptomyces sp. S045 strain. Their structures were determined based on 1D, 2D NMR spectroscopic data, HR ESI mass spectroscopy, X-ray diffraction analysis and comparison with the reported data. The new compounds were identified to be (S)-4-(1-hydroxyethyl)quinoline-2-carboxamide (1) and methyl 4-(hydroxymethyl)-2-(4-methylpentyl)-4,5-dihydrofuran-3-carboxylate (3), respectively. Their anti-bacterial and anti-type III secretion system (T3SS) activities were evaluated.

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is rapidly progressed hematologic malignancy with relapsed and refractory characteristics. Cytarabine combined with the BCL2 inhibitor venetoclax showed impressive response rates in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML), while it requires complicated administration regimens and brings added toxicity. In this work, we synthesized a mercaptopropionic acid-substituted derivative of Ara-C (Ara-SH) and used it as the trigger to fabricate a smart cytarabine and venetoclax-coloaded nanoparticle (AV-NP) through self-assembly. The AV-NP characterized with redox-responsive drug release, rapid uptake by leukemia cells, and long retention in circulation had the potential to accumulate in leukemia-enriched sites. It generated a remarkable synergistic effect with higher antileukemia activity in vitro and better safety in the hematologic system compared with free drugs and significantly improved the therapeutic effect on orthotopic AML mice in vivo. These similar results were also confirmed in primary cells from R/R-AML patients. Besides, the AV-NP has the superiority of facile fabrication and generalizability, rendering it easy for clinical translation.

Effects of hydrolysable tannins from Terminalia citrina on type III secretion system (T3SS) and their intestinal metabolite urolithin B represses Salmonella T3SS through Hha-H-NS-HilD-HilC-RtsA-HilA regulatory pathway.

Gamma-proteobacteria is a class of gram-negative opportunistic pathogens existing in the intestinal flora, often leading to diarrhea and intestinal infectious diseases, and plays an important role in maintaining intestinal homeostasis. Type III secretion system (T3SS), an important virulence system, is closely related to the adhesion and invasion and pathogenicity to host cells. Therefore, anti-virulence agents targeting T3SS are important strategies for controlling pathogenic infections. In this study, the anti-Salmonella T3SS active compounds neochebulagic acid (1), ellagic acid (2) and urolithin M5 (3) were isolated from seed extract of Terminalia citrina by activity-guided isolation method. Based on the fact that urolithins are the main and stable intestinal microbiota metabolites of hydrolysable tannins, we found that the metabolite urolithin B repressed translation and secretion of SipC through the Hha-H-NS-HilD-HilC-RtsA-HilA regulatory pathway. The results provide evidence for Terminalia seeds and ellagitannin-rich berries and nuts in regulating intestinal homeostasis and treating bacterial infection.

LINC00657 regulate colorectal carcinoma invasion and migration by enhancing heparanase expression through recruiting SMAD family member 2.

Long noncoding RNAs are master regulators of several cancer phenotypes, such as cell growth, apoptosis, and motility. This study is designed to resolve the relevance of LINC00657 with tumor invasion and migration and its action mechanism in colorectal carcinoma (CRC). LINC00657 and HPSE levels were first examined in cancerous tissues from CRC patients and CRC cells. Then functional experiments were conducted to evaluate the abilities of HCT116 and SW620 cells to proliferate, migrate, and invade when LINC00657 or HPSE was knocked down, or LINC00657 knockdown and SMAD2 overexpression were simultaneously introduced. Snail and E-cadherin levels in the CRC cells were evaluated. Next, the binding between LINC00657 and SMAD2 or between SMAD2 and HPSE was determined. LINC00657-silencing HCT116 cells were inoculated into nude mice, and the tumorigenesis and the levels of Snail and E-cadherin were evaluated. LINC00657 and HPSE were increasingly expressed in CRC. Knockdown of LINC00657 or HPSE inhibited the malignant properties of CRC cells, decreased Snail expression, and strengthened E-cadherin level. LINC00657 and HPSE could both bind to SMAD2. SMAD2 overexpression counteracted the inhibiting effect of LINC00657 silencing on HPSE expression and the growth and invasion of CRC cells. In vivo experiments further verified the suppression of LINC00657 knockdown on tumor growth and metastasis. LINC00657 recruits SMAD2 to HPSE promoter region to elevate HPSE transcription, thus accelerating CRC invasion and migration.

Urolithins and intestinal health.

There are trillions of microorganisms in the human intestine. They can react to the intestinal microenvironment by metabolizing food or producing small molecular compounds to affect the host's digestive ability and resist the risk of infection and autoimmune diseases. Many studies have revealed that intestinal flora and its metabolites play an important role in human physiology and the development of diseases. Urolithins are kind of intestinal microbiota metabolites of ellagitannins (ETs) and ellagic acid (EA) with potent biological activity in vivo. However, different individuals have different intestinal flora. According to the different metabolites from ETs and EA, it is divided into three metabo-types including UM-A, UM-B and UM-0. This paper reviews the origin of urolithins, the urolithin producing microorganisms and the effects of urolithins on regulating intestinal diseases. This review will provide a theoretical basis for the regulation of urolithins in the homeostasis of intestinal flora and a reference for the scientific utilization of urolithins and foods rich in ETs and EA.

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/ß inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIß subtypes.

Structural optimization of natural product fusaric acid to discover novel T3SS inhibitors of Salmonella.

Type III secretion system (T3SS) plays a critical role in host cell invasion and pathogenesis of Salmonella. We recently identified the mycotoxin fusaric acid (FA) as a T3SS inhibitor of Salmonella. Herein, twenty-two diphenylsulfane derivatives were designed and synthesized using FA as a lead compound through scaffold hopping. Among them, SL-8 and SL-19 possessing strong anti-T3SS and anti-invasion activity were identified as T3SS inhibitors with improvement in potency as compared to FA. The inhibitory mechanisms on SPI-1 did not depend on the HilD-HilC-RtsA-HilA or PhoP-PhoQ pathway or the assembly of T3SS needle complex. Accordingly, we proposed that the inhibitory effects of SL-8 and SL-19 on SPI-1 probably influence the formation of SicA/InvF-effector complex or other related proteins.

Specialised metabolites as chemotaxonomic markers of Coptosapelta diffusa, supporting its delimitation as sisterhood phylogenetic relationships with Rubioideae.

From the aerial extracts of Coptosapelta diffusa (Champ. ex Benth.) Steenis, twenty-one compounds were isolated and identified by means of column chromatography and NMR and MS techniques, respectively. Amongst, ten ones were determined to be undescribed compounds including six seco-iridoid glucosides (1-6), 2-(hydroxymethyl)-1,2,3,4-tetrahydroanthracene-9,10-dione (7) and three guaiane-type sesquiterpenes (15-17). Compounds 7, 8 and 9 exhibited inhibitory activities against Staphylococcus aureus ATCC25923 with MIC of 8, 4 and 8 µg/mL. The use of 1-6 (iridoids), 7-14 (anthraquinones) and 15-17 (sesquiterpenes) as chemotaxonomic markers for this species was evidenced. Structurally, 7-14 are similar to those anthraquinones isolated from other species of the family Rubiaceae, confirming their close phylogenetic relationship. Whereas, these iridoids and sesquiterpenes with unique structures provided chemotaxonomic evidence to support the genus Coptosapelta (the tribe Coptosapelteae) as a sister of the subfamily Rubioideae. These results contrast with the general producing tendency of indole alkaloids by the species of the subfamily Cinchonoideae, and merit chemotaxonomic significance for the delimitation of Coptosapelta.

Combinatorial Biosynthesis of Oxidized Combamides Using Cytochrome P450 Enzymes from Different Polycyclic Tetramate Macrolactam Pathways.

Polycyclic tetramate macrolactams (PoTeMs) are a family of natural products containing a tetramic acid moiety and a polycyclic system. Due to the valuable biological activities of different PoTeMs and the genetic simplicity of their biosynthetic genes, it is highly desirable to manipulate the biosynthesis of PoTeMs by swapping modification genes between different pathways. Herein, by combining the cytochrome P450 (CYP) enzymes from different PoTeM pathways with the combamides' biosynthetic genes, the new combamides G (3), I (5), and J (6) along with the known combamides B (1), D (2), and H (4) were identified from the recombinant strains. Combamides G (3), H (4), and J (6) displayed cytotoxic activity against human cancer cell lines. Furthermore, our results demonstrated for the first time the substrate specificity of the PoTeM-related CYPs in vivo, which will facilitate the engineered biosynthesis of other PoTeMs in the future.

Rifamycin W Analogues from Amycolatopsis mediterranei S699 Δrif-orf5 Strain.

Rifamycin W, the most predominant intermediate in the biosynthesis of rifamycin, needs to undergo polyketide backbone rearrangement to produce rifamycin B via an oxidative cleavage of the C-12/C-29 double bond. However, the mechanism of this putative oxidative cleavage has not been characterized yet. Rif-Orf5 (a putative cytochrome P450 monooxygenase) was proposed to be involved in the cleavage of this olefinic moiety of rifamycin W. In this study, the mutant strain Amycolatopsis mediterranei S699 Δrif-orf5 was constructed by in-frame deleting the rif-orf5 gene to afford thirteen rifamycin W congeners (1-13) including seven new ones (1-7). Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Presumably, compounds 1-4 were derivatized from rifamycin W via C-5/C-11 retro-Claisen cleavage, and compounds 1-3, 9 and 10 featured a hemiacetal. Compounds 5-7 and 11 showed oxygenations at various sites of the ansa chain. In addition, compounds 1-3 exhibited antibacterial activity against Staphylococcus aureus with minimal inhibitory concentration (MIC) values of 5, 40 and 0.5 µg/mL, respectively. Compounds 1 and 3 showed modest antiproliferative activity against HeLa and Caco-2 cells with half maximal inhibitory concentration (IC50) values of about 50 µM.

Long non-coding RNA SNHG12 promotes proliferation and invasion of colorectal cancer cells by acting as a molecular sponge of microRNA-16.

Long non-coding (lnc)RNA small nucleolar RNA host gene 12 (SNHG12) has an oncogenic role in various common human cancer types, including colorectal cancer (CRC). However, the detailed regulatory mechanisms of SNHG12 in CRC cells have remained largely elusive, and the investigation thereof was the purpose of the present study. Polymerase chain reaction analysis was performed to examine the expression of lncRNA and microRNA (miR). Cell Counting Kit-8 and Transwell assays were used to assess cell proliferation and invasion. A luciferase reporter assay was performed to confirm a predicted targeting association between lncRNA and miR. It was observed that SNHG12 was markedly upregulated in CRC tissues when compared with that in adjacent non-tumour tissues, and its high expression was associated with CRC progression, as well as poor prognosis of patients. In addition, the expression of SNHG12 was higher in CRC cell lines when compared with that in a normal intestinal epithelial cell line. Knockdown of SNHG12 significantly inhibited CRC cell proliferation and invasion, while ectopic overexpression of SNHG12 had the opposite effect. A Bioinformatics analysis predicted that SNHG12 and miR-16 have complementary binding sites, which was confirmed by a luciferase reporter gene assay. The expression levels of miR-16 were markedly decreased in CRC tissues and cell lines compared with those in normal tissues or cells, and were inversely correlated with the expression levels of SNHG12 in CRC tissues. Furthermore, silencing of miR-16 eliminated the suppressive effects of SNHG12 knockdown on CRC cell proliferation and invasion. In conclusion, the present study demonstrated that SNHG12 promotes CRC cell proliferation and invasion, at least in part, by acting as a molecular sponge of miR-16, suggesting that SNHG12 may be a promising therapeutic target for CRC.