Stereodivergent atom transfer radical addition of α-functionalized alkyl iodides to alkynes: a strategy for selective synthesis of both - and -iodoalkenes.

The geometrical control of atom transfer radical addition (ATRA) reactions to alkynes poses significant challenges. Herein, we present a uniform solution by developing a stereodivergent synthetic method for both isomers of the resulting alkene products, starting from the same materials. The synthesis of the thermodynamically more stable isomer utilizes the strategy of uphill catalysis while the accumulation of the less stable isomer is facilitated by a manganese-catalyzed iodo-abstraction/radical rebound process, taking advantage of its reversibility.

Lnc-Pim1 Promotes Neurite Outgrowth and Regeneration of Neuron-Like Cells Following ACR-Induced Neuronal Injury.

Decreased regenerative capacity of central nervous system neurons is the main cause for failure of damaged neuron regeneration and functional recovery. Long noncoding RNAs (lncRNAs) are abundant in mammalian transcriptomes, and many time- and tissue-specific lncRNAs are thought to be closely related to specific biological functions. The promoting effect of Pim-1 gene on neural differentiation and regeneration has been documented, but the effect and mechanism of its neighbor gene Lnc-Pim1 in regulating the response of central neurons to injury remain unclear.

Podophyllotoxin derivatives-tubulin complex reveals a potential binding site of tubulin polymerization inhibitors in α-tubulin adjacent to colchicine site.

The colchicine site of β-tubulin has been proven to be essential binding sites of microtubule polymerization inhibitors. Recent studies implied that GTP pocket of α-tubulin adjacent to colchicine sites is a potential binding site for developing tubulin polymerization inhibitors. However, the structural basis for which type of structural fragments was more beneficial for enhancing the affinity of α-tubulin is still unclear.

Heterodimers of Aromadendrane Sesquiterpenoid with Benzoquinone from the Chinese Liverwort .

Mylnudones A-G (-), unprecedented 1,10--aromadendrane-benzoquinone-type heterodimers, and a highly rearranged aromadendrane-type sesquiterpenoid (), along with four known analogs (-), were isolated from the liverwort . Compounds - and , bearing tricyclo[6.2.

Dehydroamino acid residues in bioactive natural products.

Covering: 2000 to up to 2023α,β-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,β-unsaturation in dhAAs has profound effects on the properties of these molecules.

ASIC1/RIP1 accelerates atherosclerosis via disrupting lipophagy.

Introduction: Atherosclerosis, a major contributor to cardiovascular disease, remains a significant health concern worldwide. While previous research has shown that acid-sensing ion channel 1 (ASIC1) impedes macrophage cholesterol efflux, its precise role in atherogenesis and the underlying mechanisms have remained elusive.

Objectives: This study aimed to investigate the role of ASIC1 in atherosclerosis and its underlying mechanisms.

A truncated DNA aptamer with high selectivity for estrogen receptor-positive breast cancer cells.

The estrogen receptor-positive (ER+) breast cancers constitute more than 50 % of breast cancers, seriously threatening the health of women. Unfortunately, the detection and targeted therapy of ER+ breast cancers remain a challenge. Here, a novel nucleic acid aptamer S1-4 was developed to specifically target ER+ breast cancer MCF-7 cells by using Cell-SELEX and nucleic acid truncation strategies.

Molecular insights into the catalytic promiscuity of a bacterial diterpene synthase.

Diterpene synthase VenA is responsible for assembling venezuelaene A with a unique 5-5-6-7 tetracyclic skeleton from geranylgeranyl pyrophosphate. VenA also demonstrates substrate promiscuity by accepting geranyl pyrophosphate and farnesyl pyrophosphate as alternative substrates. Herein, we report the crystal structures of VenA in both apo form and holo form in complex with a trinuclear magnesium cluster and pyrophosphate group.

Pallamins A-C, ent-labdane and pallavicinin based dimers from the Chinese liverwort Pallavicinia ambigua (mitt.) stephani.

Three unprecedented ent-labdane and pallavicinin based dimers pallamins A-C formed via [4 + 2] Diels-Alder cycloaddition, together with eight biosynthetically related monomers were isolated from Pallavicinia ambigua. Their structures were determined by the extensive analysis of HRESIMS and NMR spectra. The absolute configurations of the labdane dimers were determined by single crystal X-ray diffraction of the homologous labdane units, and C NMR and ECD calculations.

Conjugating 4β-NH-(5-Aminoindazole)-podophyllotoxin and Galectin-1-Targeted Aptamer for Synergistic Chemo-Immunotherapy of Hepatocellular Carcinoma.

By conjugating a chemotherapeutic candidate drug 4β-NH-(5-aminoindazole)-podophyllotoxin (βIZP) and an immunosuppressive protein galectin-1 targeted aptamer AP74, a chemo-immunotherapy molecule (AP74-βIZP) is developed against liver cancer. AP74-βIZP can target galectin-1 and enrich the tumor microenvironment to improve the tumor inhibition ratio by 6.3%, higher than that of βIZP in a HepG2 xenograft model.

Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors' Binding Pocket.

Although non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibit potent anti-HIV-1 activity and play an important role in the active antiretroviral therapy of AIDS, the emergence of drug-resistant strains has seriously reduced their clinical efficacy. Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs by exploiting the tolerant regions of the NNRTI binding pocket. Compounds and were demonstrated to have excellent activity (EC = 3.

Circulating galectin-3 promotes tumor-endothelium-adhesion by upregulating ICAM-1 in endothelium-derived extracellular vesicles.

The adhesion of tumor cells to vascular endothelial cells is an important process of tumor metastasis. Studies have shown that tumor could educate vascular endothelial cells to promote tumor metastasis through many ways. However, the effect of tumor cells on the functions of vascular endothelial cells-derived extracellular vesicles (H-EVs) and the mechanisms underlying their effects in tumor-endothelium adhesion in metastasis remain mysterious.

The Advances and Challenges in Enzymatic -glycosylation of Flavonoids in Plants.

Flavonoid glycosides play determinant roles in plants and have considerable potential for applications in medicine and biotechnology. Glycosyltransferases transfer a sugar moiety from uridine diphosphateactivated sugar molecules to an acceptor flavonoid via C-O and C-C linkages. Compared with O-glycosyl flavonoids, C-glycosyl flavonoids are more stable, resistant to glycosidase or acid hydrolysis, exhibit better pharmacological properties, and have received more attention.

Docking-guided rational engineering of a macrolide glycosyltransferase glycodiversifies epothilone B.

Glycosyltransferases typically display acceptor substrate flexibility but more stringent donor specificity. BsGT-1 is a highly effective glycosyltransferase to glycosylate macrolides, including epothilones, promising antitumor compounds. Here, we show that BsGT-1 has three major regions significantly influencing the glycodiversification of epothilone B based on structural molecular docking, "hot spots" alanine scanning, and site saturation mutagenesis.

Hyaluronic Acid-Modified Nanoparticles Self-Assembled from Linoleic Acid-Conjugated Chitosan for the Codelivery of miR34a and Doxorubicin in Resistant Breast Cancer.

In this study, a chitosan-based, self-assembled nanosystem that codelivered microRNA34a (miR34a) and doxorubicin (Dox) with hyaluronic acid (HA) modification (named CCmDH NPs) was developed to reverse the resistance of breast cancer (BCa) cells to Dox. The CCmDH NPs had a diameter of 180 ± 8.3 nm and a ζ potential of 16.

Improved dsDNA recombineering enables versatile multiplex genome engineering of kilobase-scale sequences in diverse bacteria.

Recombineering assisted multiplex genome editing generally uses single-stranded oligonucleotides for site directed mutational changes. It has proven highly efficient for functional screens and to optimize microbial cell factories. However, this approach is limited to relatively small mutational changes.

Biosynthesis of Chuangxinmycin Featuring a Deubiquitinase-like Sulfurtransferase.

The knowledge on sulfur incorporation mechanism involved in sulfur-containing molecule biosynthesis remains limited. Chuangxinmycin is a sulfur-containing antibiotic with a unique thiopyrano[4,3,2-cd]indole (TPI) skeleton and selective inhibitory activity against bacterial tryptophanyl-tRNA synthetase. Despite the previously reported biosynthetic gene clusters and the recent functional characterization of a P450 enzyme responsible for C-S bond formation, the enzymatic mechanism for sulfur incorporation remains unknown.

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs.

Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S.

Discovery of Polycyclic Macrolide Shuangdaolides by Heterologous Expression of a Cryptic -AT PKS Gene Cluster.

A cryptic -acyltransferase polyketide synthase biosynthetic gene cluster (80 kb) from sp. B59 was cloned and transferred into a heterologous host J1074, resulting in a class of polycyclic macrolide shuangdaolides A-D () and dumulmycin (). Heterologous expression and gene inactivation experiments allowed the identification of two biosynthetic intermediates, and , suggesting an unusual multidomain SDR oxidoreductase SdlR in charge of the formation of a rare 2-hydroxycyclopentenone moiety in this class of compounds.

Corrigendum: Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma.

[This corrects the article DOI: 10.3389/fonc.2018.

[Research progress in biosynthesis of podophyllotoxin and its derivatives].

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand.

Fatty acid oxidation: driver of lymph node metastasis.

Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown.