Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (1–9, 14–17, 19, and 20) along with 16 known compounds from E. usambarica with HIV-1 latency reversal activity. Euphordraculoate C (1) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (2) and B (3) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4β-Crotignoid K (14) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (13), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids 12–14 and 21 for the HIV-1 latency reversal activity was activation of PKC, while lignans 26 and 27 that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from E. usambarica have the potential to contribute to the development of HIV-1 eradication strategies.

Synthesis and Cytotoxic Activity of the Products of Addition of Thiophenol to Sesquiterpene Lactones

Abstract— Derivatives of sesquiterpene lactones modified at the lactone ring with a thiophenol residue have been synthesized. The resulting conjugates with thiophenol have capacity for the oxidation–elimination reaction by the action of ROS of a tumor cell with the release of initial cytotoxic lactones. It has been proposed to use the resulting sulfur-containing conjugates as ROS-activated prodrugs of sesquiterpene lactones. The antiproliferative properties of the conjugates have been examined on tumor and pseudonormal cell lines. The cytotoxicity of the conjugates is lower than that of parent lactones; however, in some cases, as with the conjugates of alantolactone with artemisiten, it remains moderate in all tumor cell lines tested.

The Komagataeibacter europaeus GqqA is the prototype of a novel bifunctional N-Acyl-homoserine lactone acylase with prephenate dehydratase activity

Previously, we reported the isolation of a quorum quenching protein (QQ), designated GqqA, from Komagataeibacter europaeus CECT 8546 that is highly homologous to prephenate dehydratases (PDT) (Valera et al. in Microb Cell Fact 15, 88. 10.1186/s12934-016-0482-y, 2016). GqqA strongly interfered with N-acyl-homoserine lactone (AHL) quorum sensing signals from Gram-negative bacteria and affected biofilm formation in its native host strain Komagataeibacter europaeus. Here we present and discuss data identifying GqqA as a novel acylase. ESI–MS–MS data showed unambiguously that GqqA hydrolyzes the amide bond of the acyl side-chain of AHL molecules, but not the lactone ring. Consistent with this observation the protein sequence does not carry a conserved Zn2+ binding motif, known to be essential for metal-dependent lactonases, but in fact harboring the typical periplasmatic binding protein domain (PBP domain), acting as catalytic domain. We report structural details for the native structure at 2.5 Å resolution and for a truncated GqqA structure at 1.7 Å. The structures obtained highlight that GqqA acts as a dimer and complementary docking studies indicate that the lactone ring of the substrate binds within a cleft of the PBP domain and interacts with polar residues Y16, S17 and T174. The biochemical and phylogenetic analyses imply that GqqA represents the first member of a novel type of QQ family enzymes.

Simulation and Computational Study of Graphene Oxide Nanocarriers Loaded in the Absorption and Release of the Anticancer Drug of Camptothecin

The structure of nano- graphene oxide, due to its special properties such as hydrophilicity, special surface and suitable biocompatibility, the possibility of high loading of hydrophilic and hydrophobic drugs, has attracted special attention in drug release. In this study, after simulating and optimizing the structure of nano-graphene and then nano-graphene oxide (NGO), it was used to load the anti-cancer drug of camptothecin (CA) in aqueous medium and the optimal conditions for achieving maximum loading efficiency of the drug were investigated. Due to the structure of the drug, there are two forms of lactone ring and carboxylate, which if the lactone ring form is predominant, the effectiveness of the drug is increased, which depends on the pH of environment. The calculated thermodynamic and structural results show that the solubility of the drug in relation to nano-graphene and its lactone ring state are maintained by using nano-graphene oxide. By folic acid as an intermediate in aqueous medium, the drug is released to form of lactone ring and is increased the effectiveness of drug. Lactony is maintained the drug structure and is increased the drug effectiveness. The results show that the presence of the ring in the drug structure and its binding to the mediator of folic acid to nano-graphene oxide is a stabilizing factor of keto tautomer. The calculation of vibrational frequencies show that the presence of folic acid intermediate reduces the vibrational frequency of the hydroxyl group (OH) so that its absorption energy (Ead) is equal to the lowest value 65.24 a.u.

Macrolides: From Toxins to Therapeutics

Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most well characterized macrolides are toxins produced by marine bacteria, sea sponges, and other species. Many marine macrolide toxins act as biomimetic molecules to natural actin-binding proteins, affecting actin polymerization, while other toxins act on different cytoskeletal components. The disruption of natural cytoskeletal processes affects cell motility and cytokinesis, and can result in cellular death. While many macrolides are toxic in nature, others have been shown to display therapeutic properties. Indeed, some of the most well known antibiotic compounds, including erythromycin, are macrolides. In addition to antibiotic properties, macrolides have been shown to display antiviral, antiparasitic, antifungal, and immunosuppressive actions. Here, we review each functional class of macrolides for their common structures, mechanisms of action, pharmacology, and human cellular targets.

The Komagataeibacter europaeus GqqA is the prototype of a novel bifunctional N-Acyl-homoserine lactone acylase with prephenate dehydratase activity

Previously, we reported the isolation of a quorum quenching protein (QQ), designated GqqA, from Komagataeibacter europaeus CECT 8546 that is highly homologous to prephenate dehydratases (PDT) 1. GqqA strongly interfered with N-acyl-homoserine lactone (AHL) quorum sensing signals from Gram-negative bacteria and affected biofilm formation in its native host strain Komagataeibacter europaeus. Here we present and discuss data identifying GqqA as a novel acylase. ESI-MS-MS data showed unambiguously that GqqA hydrolyzes the amide bond of the acyl side-chain of AHL molecules, but not the lactone ring. Consistent with this observation the protein sequence does not carry a conserved Zn2+ binding motif, known to be essential for metal-dependent lactonases, but in fact harboring the typical periplasmatic binding protein domain (PBP domain), acting as catalytic domain. We report structural details for the native structure at 2.5 Å resolution and for a truncated GqqA structure at 1.7 Å. The structures obtained highlight that GqqA acts as a dimer and complementary docking studies indicate that the lactone ring of the substrate binds within a cleft of the PBP domain and interacts with polar residues Y16, S17 and T174. The biochemical and phylogenetic analyses imply that GqqA represents the first member of a novel type of QQ family enzymes.

New Bromo- and Iodo-Hydroxylactones with Two Methyl Groups Obtained by Biotransformation of Bicyclic Halolactones

The subject of the research was to determine the ability of the filamentous fungi to biotransform bicyclic halolactones containing two methyl groups in their structure. By chemical synthesis three bicyclic halolactones with two methyl groups, one in the cyclohexane ring and one in the lactone ring, were obtained: 2-chloro-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, 2-bromo-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, and 2-iodo-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one. These compounds were formed as mixtures of two diastereoisomers. The obtained halolactones (as mixture of two diastereoisomers) were subjected to screening biotransformation with the use of eight strains of filamentous fungi: Fusarium culmorum AM10, F. avenaceum AM12, F. semitectum AM20, F. solani AM203, Absidia coerulea AM93, A. cylindrospora AM336, Penicillium chermesinum AM113, P. frequentans AM351. Two of the substrates, 2-bromo-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one and 2-iodo-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, were hydroxylated without removing the halogen atom from the molecule, giving 2-bromo-7-hydroxy-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, 2-bromo-5-hydroxy-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, and 2-iodo-7-hydroxy-4,7-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one as products. The hydroxylation capacity was demonstrated by strains of Absidia cylindrospora AM336, Fusarium avenaceum AM12, and F. solani AM203. The structures of all lactones were determined on the basis spectroscopic data.