First total synthesis of type II abyssomicins: (±)-abyssomicin 2 and (±)-neoabyssomicin B.

The intramolecular Diels-Alder reaction (IMDA) of a butenolide derivative, as an entry to the type II abyssomicin scaffold, and the total synthesis of (±)-abyssomicin 2 and (±)-neoabyssomicin B are reported for the first time. A facile route to the IMDA precursor, the formation of a type I intermediate and two paths to (±)-neoabyssomicin B are also discussed.

Interferon lambda1/IL-29 and inorganic polyphosphate are novel regulators of neutrophil-driven thromboinflammation.

Neutrophils and neutrophil-released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN-λ1/IL-29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST-segment elevation myocardial infarction (STEMI), we show that IFN-λ1/IL-29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet-neutrophil interaction plays a major role in NET-induced thromboinflammation, we further studied how IFN-λ1/IL-29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet-derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN-λ1/IL-29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl3 -induced arterial thrombosis that IFN-λ2/IL-28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN-λ1/IL-29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hyperforin and deoxycohumulone as a larvicidal agent against Culex pipiens (Diptera: Culicidae).

The larvicidal effect of hyperforin (1), a bioactive compound of Hypericum perforatum, and deoxycohumulone (2) (biosynthetic precursor of hyperforin) were evaluated against Culex pipiens (Diptera: Culicidae) for the first time. All the acetate analogues (3-6) of hyperforin (1) and deoxycohumulone (2) were also synthesized and bioassayed to provide information on structural requirements for the tested compounds. Larvicidal results revealed that hyperforin (1) and deoxycohumulone (2) exhibited potent activity with LC50 value of 26.72 and 51.03 mg L(-1), respectively. The monoacetyl-deoxycohumulone (4) displayed lower activity with LC50 value of 135.92 mg L(-1), while all other acetate analogues were inactive at concentrations even as high as 150 mg L(-1), indicating that the free hydroxyl groups are essential for the larvicidal activity. The mortality values were increased, more than 80%, when 10 mg L(-1) piperonyl butoxide were added in hyperforin (1) or deoxycohumulone (2) bioassays. Finally, sub-lethal survival analysis is conducted for three doses of hyperforin (1) and deoxycohumulone (2) and results are discussed.

Bioefficacy of acyclic monoterpenes and their saturated derivatives against the West Nile vector Culex pipiens.

Twenty acyclic monoterpenes with different functional groups (acetoxy, hydroxyl, carbonyl and carboxyl) bearing a variable number of carbon double bonds were assayed as repellent and larvicidal agents against the West Nile vector Culex pipiens. Seven of them were derivatives that were synthesized through either hydrogenation or oxidation procedures. All repellent compounds were tested at the dose of 1mgcm(-2) and only neral and geranial were also tested at a 4-fold lower dose (0.25mgcm(-2)). Repellency results revealed that geranial, neral, nerol, citronellol, geranyl acetate and three more derivatives dihydrolinalool (3), dihydrocitronellol (5) and dihydrocitronellyl acetate (6) resulted in no landings. Based on the LC50 values the derivative dihydrocitronellyl acetate (6) was the most active of all, resulting in an LC50 value of 17.9mgL(-1). Linalyl acetate, citronellyl acetate, neryl acetate, geranyl acetate, dihydrocitronellol (5), dihydrocitronellal (7), citronellol, dihydrolinalyl acetate (2), citronellic acid and tetrahydrolinalyl acetate (1) were also toxic with LC50 values ranging from 23 to 45mgL(-1). Factors modulating toxicity have been identified, thus providing information on structural requirements for the selected acyclic monoterpenes. The acetoxy group enhanced toxicity, without being significantly affected by the unsaturation degree. Within esters, reduction of the vinyl group appears to decrease potency. Presence of a hydroxyl or carbonyl group resulted in increased activity but only in correlation to saturation degree. Branched alcohols proved ineffective compared to the corresponding linear isomers. Finally, as it concerns acids, data do not allow generalizations or correlations to be made.

An unusual Michael-induced skeletal rearrangement of a bicyclo[3.3.1]nonane framework of phloroglucinols to a novel bioactive bicyclo[3.3.0]octane.

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (16) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (17), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (1), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ(7,10)-double bond was examined under several conditions to explain the above results.

A short biomimetic approach to the fully functionalized bicyclic framework of type A acylphloroglucinols.

A biomimetic approach toward type A polyprenylated acylphloroglucinols (PPAPs) is described. The method is based on a C-alkylation-cation cyclization reaction sequence, leading to a convenient buildup of molecular complexity, employing the simple and readily available deoxycohumulone and an appropriately functionalized hydroxy halide. Thus, a versatile construction of the fully functionalized bicyclic framework of type A PPAPs (5) was achieved.

Larvicidal activity of naturally occurring naphthoquinones and derivatives against the West Nile virus vector Culex pipiens.

Concentration-dependent mortality effects were observed for three pure synthetic natural products (alkannin, shikonin, and shikalkin) and three acetylated derivatives of shikonin against Culex pipiens (Culicidae: Diptera) for the first time. The larvicidal properties of all naphthoquinones were evaluated under laboratory conditions against the larvae of the mosquito species C. pipiens biotype molestus, the anthropophilic biotype of the C. pipiens mosquito species. Experimental data of the tested toxicity of quinones revealed generally high efficacy where shikonin (3.9 mg/L) was the most active followed by shikalkin (8.73 mg/L) and alkannin (12.35 mg/L). The insecticidal performance of shikonin-acetylated derivatives was also investigated, aiming at the same time in the establishment of the relationships between the structure and the activity of shikonin-type compounds with larvicidal activity against C. pipiens. Results indicated that naphthoquinones, compared with other natural compounds with larvicidal activity, are very toxic against mosquito larvae and could be a potential source of natural larvicidal substances. Finally, bioassays with shikonin derivatives also revealed that although hydroxylic groups seem to play a secondary role in efficacy, the quinone moiety is essential.

Influence of the microencapsulated pheromone from aged infusion as an oviposition medium of the West Nile virus vector Culex pipiens.

The main tendency for the control of West Nile virus vectors, without the presence of disease, is to perform integrated programs minimizing chemicals by using environmentally friendly substances which act as oviposition attractants such as oviposition pheromones and infusions. This is the first time that an aged infusion is combined with aged pheromone (microencapsulated). Initially, three common plants in Greece were evaluated as a potential oviposition medium: Oxalis pes-carpae, Jasminum polyanthum, and Avena barbata. All revealed an excellent oviposition attractancy which was more than 80%. O. pes-carpae was used for further investigation and attractancy over time was also studied. Finally, the combination of the synthetic pheromone (6-acetoxy-5-hexadecanolide) with the O. pes-carpae infusion revealed a synergistic effect only for the first day. This project was a first detection for the potential use of microencapsulated synthetic pheromone with infusion and results are discussed.

Open-chain half-bastadins mimic the effects of cyclic bastadins on calcium homeostasis in cultured neurons.

Constraining the catechol aryl ether moiety of bastadins by incorporation into a macrocyle is not necessary in order to mimic the effects of these marine natural products on neuronal calcium homeostasis. Simple, acyclic analogs that embody the 'western' or 'eastern' parts of bastadins were found to evoke comparable responses with bastadin 5.

Attract-and-kill strategy. Laboratory studies on hatched larvae of Culex pipiens.

The attract-and-kill strategy is a new pest management technique that presupposes the intelligent combination of an attracting agent (e.g. pheromone) and a killing agent (e.g. insecticide). In the present study, the potential combination of the microencapsulated synthetic oviposition pheromone 6-acetoxy-5-hexadecanolide with an insecticide has been tested. Initially, polyurea microcapsules containing 6-acetoxy-5-hexadecanolide, the synthetic mixture of diastereomers of the oviposition pheromone of the mosquito species Culex quinquefasciatus Say (Diptera: Culicidae), were studied. Laboratory bioassays were performed to confirm the bioactivity of the microencapsulated pheromone on the oviposition activity of Culex pipiens L. biotype molestus Førskal (Diptera: Culicidae) with the aim of determining the optimum dose for oviposition response. Its effect was dose dependent, revealing an optimum dose of 300 mg of dried microcapsules. Attractancy over time was also studied. The microencapsulated pheromone was found to be sufficiently attractive to gravid female mosquitoes for a period of 40 days. Finally, the combination of the synthetic pheromone with the control agent temephos showed both an acceptable oviposition activity and sufficient larvicidal effect.

A short and convenient chemical route to optically pure 2-methyl chromanmethanols. Total asymmetric synthesis of beta-, gamma-, and delta-tocotrienols.

With use of inexpensive commercially available raw materials, chromanmethanol precursors to the natural beta-, gamma-, and delta-tocotrienols have been prepared in high yield. Enzymatic resolution afforded chiral chromanmethanols in high enantiomeric excess. Subsequent attachment of the farnesyl side chain was high yielding, thus allowing the preparation of asymmetric beta-, gamma-, and delta-tocotrienols in one final step wherein simultaneous deprotection of the phenol and removal of the sulfone group occurs. This chemistry provides the first synthesis of natural-series beta-tocotrienol.

Synthetic bastadins modify the activity of ryanodine receptors in cultured cerebellar granule cells.

Although the interactions of several natural bastadins with the RyR1 isoform of the ryanodine receptor in sarcoplasmic reticulum has been described, their structure-dependent interference with the RyR2 isoform, mainly expressed in cardiac muscle and brain neurons, has not been studied. In this work, we examined calcium transients induced by natural bastadin 10 and several synthetic bastadins in cultured cerebellar granule cells known to contain RyR2. The fluorescent calcium indicator fluo-3 and confocal microscopy were used to evaluate changes in the intracellular Ca(2+) concentration (Ca(i)), and the involvement of ryanodine receptors was assessed using pharmacological tools. Our results demonstrate that apart from the inactive BAST218F6 (a bisdebromo analogue of bastadin 10), synthetic bastadin 5, and synthetic analogues BAST217B, BAST240 and BAST268 (at concentrations >20 microM) increased Ca(i) in a concentration-dependent, ryanodine- and FK-506-sensitive way, with a potency significantly exceeding that of 20 mM caffeine. Moreover, the same active bastadins at a concentration of 5 muM in the presence of ryanodine prevented a thapsigargin-induced increase in Ca(i). These results indicate that bastadins, acting in a structure-dependent manner, modify the activity of RyR2 in primary neuronal culture and provide new information about structure-related pharmacological properties of bastadins.

Synthesis and biological evaluation of novel steroid-modified ether phospholipids.

Platelet activating factor is one of the most potent inflammatory ether phospholipid mediators known and structurally modified analogues are of considerable interest as potential therapeutic preparations. Inspired by the proposed structure for a novel endogenous hydroxy-PAF analogue isolated recently from gingival crevicular fluid, we designed and prepared two novel steroid-modified ether phospholipids. These two novel compounds exhibit marked chemical and biological similarities to their endogenous prototype and they antagonize it being less active in inducing washed platelet aggregation through PAF receptors.

Oviposition responses of culex pipiens to a synthetic racemic Culex quinquefasciatus oviposition aggregation pheromone.

The oviposition pheromone of Culex quinquefasciatus was synthesized in a racemic form in a simple (five steps), efficient, high yielding (45% total yield), and low cost way (use of relatively low cost reagents). Our synthetic racemic pheromone (SRP) was tested in the laboratory for its bioactivity on Culex pipiens biotype molestus, which is a member of the species complex that Culex quinquefasciatusbelongs. In the testing conditions, bioactivity at the doses of 0.01, 0.1, 1, and 10 microg per cage was found with the best bioactivity achieved at 1 mug per cage. The effectiveness of our SRP offers a capable tool for improving mosquito oviposition traps for surveillance or even control programs.

Solid-phase total synthesis of (-)-Phenylhistine and (-)-Aurantiamine. Synthesis of a diverse dehydro-2,5-diketopiperazine library. Part II.

The preparation of solid supported glycine phosphonate and its utilization for the total synthesis of two natural products is presented. The proposed protocol combines diversity with accessibility and speed, which makes this scaffold suitable for automated parallel synthesis and combinatorial chemistry. The preparation of a small library of dehydro-2,5-diketopiperazines, combining several natural amino acids with diverse heterocycles (including thiazoles, pyridines, indoles and imidazoles), is also demonstrated.

Total asymmetric synthesis of (-)-Phenylhistine, (-)-Aurantiamine and related compounds. Part I.

A new general, short, and efficient strategy for the construction of dehydro-diketopiperazines was developed. Horner-Emmons type coupling between a phosphinyl glycine ester and a formyl heterocycle is the key coupling reaction, which proceeds in good-to-excellent yields on several sterically-hindered substrates. Moreover, racemization of the parent L-amino acids is avoided as a result of the mild basic conditions used. The selection of the NH protective group of the formyl heterocycle was crucial. N-tosylated heterocycles proved ideal for this reaction sequence. Thus, the title compounds, (-)-Phenylhistine and (-)-Aurantiamine, were prepared in high yield (four steps, 47% overall) and optical purity. Furthermore, the synthesis of unnatural derivatives including an indole analogue was successfully completed.

A general method for the synthesis of bastaranes and isobastaranes: first total synthesis of bastadins 5, 10, 12, 16, 20, and 21.

A general strategy for the synthesis of twenty naturally occurring bastadins (all but bastadin 3) is presented. A key retrosynthetic disconnection of the two amide bonds, common in all target molecules, bisects the macrocyclic core into two diaryl ether fragments, an alpha,omega-diamine (western part) and an alpha,omega-dicarboxylic acid (eastern part). Efficient preparation of the synthetically challenging o-mono or dibromo-substituted diaryl ether linkages was achieved employing the diaryl iodonium salt method. Regarding the western part, variations of the aliphatic chain were more efficiently secured by the preparation of two different alpha,omega-aminonitrile moieties. Cobalt boride mediated reduction of the nitrile functionality established the required diamines and, at the same time, provided the necessary variation of the aromatic-ring bromination pattern. Regarding the eastern part, two different dicarboxyl precursors had to be prepared in order to accommodate bromination-pattern variations. Coupling and subsequent macrolactamization of different combinations of these key intermediates may lead at will to any member of this family of marine natural products. Four bastaranes (bastadins 5, 10, 12 and 16) and two isobastaranes (bastadins 20 and 21) were synthesized as a demonstration of the flexibility and efficiency of the approach presented.

Novel stereocontrolled approach to syn- and anti-oxepene-cyclogeranyl trans-fused polycyclic systems: asymmetric total synthesis of (-)-Aplysistatin, (+)-Palisadin A, (+)-Palisadin B, (+)-12-hydroxy-palisadin B, and the AB ring system of adociasulfate-2 and toxicol A.

A new stereocontrolled method for the formation of trans-anti cyclogeranyl-oxepene systems is described. The demanding stereochemistry is secured by stereoselective coupling of a cyclogeranyl tertiary alcohol with a 1,2-unsymmetrically substituted epoxide, while the formation of the highly strained oxepene is achieved employing ring-closing metathesis. Since the stereochemistry of the trans-fused 6,7-ring system is determined by the epoxide, the method also allows the construction of trans-syn 6,7-ring systems. This approach leads to the synthesis of the AB fragment of Adociasulfate-2 and Toxicol A, for the first time. The flexibility and efficiency of the presented strategy is demonstrated by the total asymmetric synthesis of (-)-Aplysistatin, (+)-Palisadin A, (+)-12-hydroxy-Palisadin B, and (+)-Palisadin B, employing two similar key intermediates.

First total synthesis of trans- and cis-resorcylide: remarkable hydrogen-bond-controlled, stereospecific ring-closing metathesis.

[reaction: see text] Stereospecific synthesis of the pair of natural macrolides, trans- and cis-resorcylide, was performed using ring-closing metathesis on dienes 3 and 4, which lack or feature an intramolecular H-bond, respectively. An effective Stille carbonylative coupling of benzyl chlorides 11 and 15 was employed for their preparation. The influence of intramolecular H-bonding on the interconversions of resorcylides was also studied.