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Juggling between reactivity and selectivity, free radical oxidation offers a unique means to synthesize natural products in a direct and efficient way. The case study of sesquiterpenes is illustrative of how modern total synthesis should be conducted.

Pyrrole-proline diketopiperazine (DKP) acts as an efficient mediator for the reduction of dioxygen by Hantzsch ester under mild conditions to allow the aerobic metal-free epoxidation of electron-rich alkenes. Mechanistic crossovers are underlined, explaining the dual role of Hantzsch ester as a reductant/promoter of the DKP catalyst and a simultaneous competitor for the epoxidation of alkenes when HFIP is used as a solvent. Expansion of this protocol to the synthesis of allylic alcohols was achieved by adding a catalytic amount of selenium dioxide as an additive, revealing a superior method to the classical application of t-BuOOH as a selenium dioxide oxidant.

The ability of natural and non-natural dipeptides to act as activators of dioxygen in the absence of metallic co-catalysts is reported here. Proline derived 2,5-diketopiperazines were found active ...

The development of a divergent scaffold able to access an array of diverse natural sesquiterpenoids is described. The route unifies the scope of previously reported plans of our group to allow the scalable synthesis of 8,12-furo and lactone sesquiterpenoid carbocyclic cores of elemanes, germacranes, guaianes, cadinanes, lindenanes and myliols. The formal syntheses of furogermenone, methyl-curdionolide, zedoarol, qweicurculactone, lindenene and sarcandralactone A are reported.

Divergent synthesis is a powerful but yet underdeveloped method to address the usual drawbacks of poor supply and confined diversity in the total synthesis of natural products. Herein, we describe the rational design behind the selection and the synthesis of a divergency scaffold for sesquiterpenoid lactones synthesis, as a case study, which provides access to a rich collection of carbocycles in different oxidation states within 8,12-sesquiterpenoids through simple, scalable transformations.

We have recently described the synthesis of strained carbocyclic sesquiterpenoid motifs through a highly regioselective cycloisomerization of common enyne acetates, in the presence of platinum(ii) and gold(i) chlorides as catalysts. In this work, the mechanisms of these cyclization reactions have been studied by means of DFT methods. At the outset of the reactions, the propargyl substrates suffer 1,2- or 1,3-acetate rearrangements, which compete for the formation of a metal-carbene or a vinyl-metal species, respectively. These intermediates are the resting states of the cycles towards the formation of lindenane or myliol core structures. The DFT studies have revealed the energetics of the two migration processes, as well as the reasons for some of the key experimental observations, such as the syn/anti preference in the formation of the cyclopropane rings, the different reactivities of substrates containing furan or lactone moieties, and the different outcomes of the reactions when Pt(ii) and Au(i) salts are used.

Monooxygenases are not only some of the most versatile machineries in our lives, but also some of the most explored enzymes in modern organic synthesis. They provide knowledge and inspiration on how the most abandoned oxidant, dioxygen, can be activated and utilized to deliver selective oxidations. This review presents an outline in the mechanisms that Nature uses to succeed in these processes and recent indicative examples on how chemists use this knowledge to develop selective oxidation protocols based on dioxygen as the terminal oxidant.1 Introduction2 Monooxygenases2.1 Metal-Based Monooxygenases2.1.1 Cytochromes2.1.2 Copper-Dependent Monooxygenases2.1.3 Heme-Independent Iron Monooxygenases2.1.4 Pterin-Dependent Monooxygenases2.2 Metal-Free Monooxygenases2.2.1 Flavin-Dependent Monooxygenases2.2.2 Systems without Cofactors3 Biomimetic Aerobic Oxidations3.1 Aerobic Oxidations Based on Metal Catalysts3.1.1 Epoxidations and Allylic Oxidations3.1.2 Oxidations of Unactivated Carbon Atoms and Benzylic Oxidations3.1.3 Oxidations of Aryl Groups3.1.4 Heteroatom Oxidations3.2 Aerobic Oxidations Based on Organocatalysts3.2.1 Baeyer–Villiger Oxidations3.2.2 Oxidations of Aryl Groups3.2.3 Heteroatom Oxidations4 Conclusion

The objective of this study was to assess the in vitro transdermal permeation of a model macromolecular compound namely; fluorescein isothiocyanate - dextran 4 kDa (FD-4) across full thickness human skin by means of chemical enhancers. For this purpose, two sesquiterpenes derived from farnesol were synthesized and further evaluated. Transport studies were conducted using vertical Franz diffusion cells followed by tape stripping in an attempt to examine the disposition of FD-4 on and within the skin. The transport of FD-4 across skin was significantly enhanced in the presence of farnesol and two of its derivatives: A 3.02, 2.67 and 3.74-fold increase was observed compared to a control formulation free of sesquiterpenes. Light microscopy studies showed detachment of the superficial layers and in some cases loosening and swelling of cell layers. Differential scanning calorimetry (DSC) studies of stratum corneum (SC) sheets treated with the sesquiteprenes indicated that enhanced permeation of FD-4 was mainly achieved by disruption and fluidization of the SC lipid bilayers whereas infrared spectroscopy (AT-FTIR) data indicated significant decreases in peak intensity. The results showed that the co-administration of selected sesquiterpenes with FD-4 increased its transport across the skin and might be advantageous for transdermal delivery of macromolecules.

A simple protocol involving the activation of DMSO by chlorotrimethysilane is described for the chemoselective chlorination of polyprenoids. The proposed protocol provides a versatile and scalable alternative to existing routes for accessing useful synthetic synthons for the synthesis of complex terpenoids.

The first total synthesis of the antimicrobial natural product lynamicin D has been developed using a Suzuki coupling to construct the bisindole pyrrole skeleton. An evaluation of the biological activity of lynamicin D reveals that it has a minor effect on cell viability but it can modulate splicing of pre-mRNAs. We provide evidence that this effect is mainly due to the ability of lynamicin D to alter the levels of SRPK1, the key kinase involved in both constitutive and alternative splicing.

Tosylhydrazones under palladium catalysis were found to perform cross-coupling reactions with 4-hydroxy-2-pyridones. The umpolung-like reactivity, between the α-carbon of tosylhydrazone and the 3-position of the heterocycle, which is observed in the obtained products, indicates the directed sp3-CH-activation of an alkylated phenol intermediate by the pendant 3-palladated heterocycle. The reaction and its intercepted variants are surveyed in their scope, allowing the synthesis of inaccessible 3-carbocyclic pyridones in moderate to excellent yields.

Phenoxazines are an important class of heterocycles, which are emerging in the field of medicinal chemistry. They exhibit numerous biological activities, including antiviral, anticancer, anti-Alzheimer, antidiabetic, antioxidant, anti-inflammatory, antibiotic and many more. The present review focuses on the chemistry along with the medicinal applications of the phenoxazine moiety, in order to provide a greater insight for the development of future phenoxazine therapeutics.

The present study aimed to assess the pharmacological anticancer profile of three natural and five synthetic sesquiterpenes developed by total chemical synthesis. To this end, their properties at the cellular and molecular level were evaluated in a panel of normal and cancer cell lines. The results obtained by performing cytotoxicity assays and gene expression analysis by reverse transcription-quantitative polymerase chain reaction showed that: i) Among the sesquiterpene derivatives analyzed, VDS58 exhibited a notable anticancer profile within attached (U-87 MG and MCF-7) and suspension (K562 and MEL-745) cancer cell cultures; however, U-87 MG cells were able to recover their proliferation capacity rapidly after 48 h of exposure; ii) gene expression profiling of U-87 MG cells, in contrast to K562 cells, showed a transient induction of cyclin-dependent kinase inhibitor 1A (CDKN1) expression; iii) the expression levels of transforming growth factor β1 (TGFB1) increased after 12 h of exposure of U-87 MG cells to VDS58 and were maintained at this level throughout the treatment period; iv) in K562 cells exposed to VDS58, TGFB1 expression levels were upregulated for 48 h and decrease afterwards; and v) the re-addition of VDS58 in U-87 MG cultures pretreated with VDS58 resulted in a notable increase in the expression of caspases (CASP3 and CASP9), BCL2‑associated agonist of cell death (BAD), cyclin D1, CDK6, CDKN1, MYC proto-oncogene bHLH transcription factor (MYC), TGFB1 and tumor suppressor protein p53. This upregulation persisted only for 24 h for the majority of genes, as afterwards, only the expression of TGFB1 and MYC was maintained at high levels. Through bioinformatic pathway analysis of RNA-Seq data of parental U-87 MG and K562 cells, substantial variation was reported in the expression profiles of the genes involved in the regulation of the cell cycle. This was associated with the differential pharmacological profiles observed in the same cells exposed to VDS58. Overall, the data presented in this study provide novel insights into the molecular mechanisms of action of sesquiterpene derivatives by dysregulating the expression levels of genes associated with the cell cycle of cancer cells.

The first direct C-3 alkenylation of N-substituted-4-hydroxy-2-pyridones with unactivated alkenes has been achieved under conventional palladium acetate catalysis. The presented protocol enables the efficient production of functionalized furo[3,2-c]-pyridones-2 when terminal alkenes are utilized and 3-alkenyl-4-hydroxy-2-pyridones when more substituted reaction partners are involved. The mild reaction conditions allow easy, scalable access to pyridone derivatives that resemble core structures isolated from natural alkaloids.

A common enyne scaffold, resembling the structures of natural elemanes was found to be an excellent substrate for highly regioselective cycloisomerizations to produce diverse cyclopropane sesquiterpenoids. Platinum-catalysis was utilized to produce either lindenane or myliol cores, found in natural products, starting from enyne acetate 10 and its corresponding allene 12 respectively. Based on this concept, a second generation strategy allows the formal synthesis of sarcandralactone A.

A P-C bond-forming reaction between silyl phosphonites and Morita-Baylis-Hillman acetates (MBHAs) is explored as a general alternative towards medicinally relevant β-carboxyphosphinic structural motifs. Conversion rates of diversely substituted MBHAs to phosphinic acids 9 or 14 that were recorded by using (31) P NMR spectroscopy revealed unexpected reactivity differences between ester and nitrile derivatives. These kinetic profiles and DFT calculations support a mechanistic scenario in which observed differences can be explained from the "lateness" of transition states. In addition, we provide experimental evidence suggesting that enolates due to initial P-Michael addition are not formed. Based on the proposed mechanistic scenario in conjunction with DFT calculations, an interpretation of the E/Z stereoselectivity differences between ester and nitriles is proposed. Synthetic opportunities stemming from this transformation are presented, which deal with the preparation of several synthetically capricious phosphinic building blocks, whose access through the classical P-Michael synthetic route is not straightforward.

A non-natural hydroxy-elemane was found amenable to divergent transformations, producing either polyunsaturated guaianes under basic, oxygen-free conditions, or oxidized furogermacranes when anionic oxy-Cope reaction quenched by an oxidant is employed. Based on these findings, the first total syntheses of zedoarol and gweicurculactone are reported.

Purpose A 52-year-old woman who had undergone enucleation of the left eye at the age of 7 years for posterior uveal melanoma, had no further problems until 45 years later, when she developed a multifocal malignancy of the ipsilateral orbit. Methods Case report. Results MRI documented the presence of nodular multiple masses in the anophthalmic socket suggesting possible metastatic disease. Hepatic examination and ultrasound evaluation, CT scan of the thorax and bone scintigraphy excluded other sites of metastatic lesions. She underwent excissional of the 3 distinct tumors, 2 inferiorly and one superiorly in the anophthalmic socket. After surgery she received proton beem radiotherapy in the anopthalmic socket for a total of 4.600rads. Histopathology documented malignant melanoma of the orbit characterized by epitheliod cells. Conclusions The long interval between recognition of the primary tumor and enucleation and the appearance of clinically manifest metastatic disease in the ipsilateral orbit is the longest reported in the literature to date. A similar case of metastatic choroidal melanoma to the contralateral orbit 40 years after enucleation has been reported by Coupland (1996).

The direct arylation of N-substituted-4-hydroxy-2-pyridones with aryl boronic acids has been achieved under palladium catalysis. The mild reaction conditions applied in this method and the use of a conventional catalytic system offer an attractive protocol for the efficient synthesis of a variety of 3-arylated products.

The first direct C-3 alkenylation of N-substituted-4-hydroxy-2-pyridones with unactivated alkenes has been achieved under conventional palladium acetate catalysis. The presented protocol enables the efficient production of functionalized furo[3,2-c]-pyridones-2 when terminal alkenes are utilized and 3-alkenyl-4-hydroxy-2-pyridones when more substituted reaction partners are involved. The mild reaction conditions allow easy, scalable access to pyridone derivatives that resemble core structures isolated from natural alkaloids.

The synthesis of hydroxyelemane 5 from (R)-carvone and its utilization as a common synthetic scaffold to produce structurally diverse germacrane and guaiane sesquiterpenes are described. A highly enantio- and stereoselective biomimetic tandem oxy-Cope/ene rearrangement was used as the key reaction to access the 10-membered macrocyclic core of germacranes and the condensed 5-7 carbocycles of guaiane sesquiterpenes. Additionally, reactions of furanoguaianes under acidic or oxidizing reagents have been investigated, and preliminary results of these conversions are presented.

Application of a tandem Knoevenagel/6π-electrocyclization sequence is able to produce highly substituted pyranopyridones from moderate to high yields in a one-step reaction. High diasteroselectivity is observed in some cases and was rationalized on the basis of the thermodynamic control of the evidenced reversibility of a 6π-electrocyclization reaction. Numerous examples are provided establishing a novel entry in natural product-like structures of pyranopyridone alkaloids.

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Pre- vious rational design approaches of RNA-targeting small mole- cules have been mainly concentrated on direct functionaliza- tion of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These an- alogues are able to mimic many of the interactions of the nat- ural products for the A-site, as proven by their obtained bind- ing affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic pro

Although biomimetic approaches have proven capable of converting resveratrol (1) concurrently into many of the more complex oligomers produced by plants throughout the world (such as 2-10), methods to access single members of the family have proven far more difficult to identify. Herein is described a strategy-level solution based on the use of a common building block, one distinct from Nature's starting material, that can participate in a variety of highly selective, reagent-controlled reaction cascades. These endeavors have led to the controlled synthesis of 25 natural products and analogues, molecules whose architectures encompass nearly all the carbogenic diversity of the resveratrol family.

In the current study, the ex vivo permeation of ropinirole hydrochloride (RH) across porcine buccal mucosa in the presence of three permeation enhancers, namely N-trimethyl chitosan (TMC) (positively charged) a chitosan derivative, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) (negatively charged) and hydroxypropyl-β-cyclodextrin (HP-β-CD) (neutral), was investigated. Buccal permeation studies were conducted using Franz diffusion cells. Cumulative amounts of RH were plotted versus time. The presence of the permeation enhancers significantly increased the transport of the drug across the porcine buccal epithelium compared to its plain congener (RH solution). The rank order effect of the permeation enhancers for the transport of RH across buccal epithelium was TMC ≥ SBE-β-CD > HP-β-CD > RH solution. The presence of TMC increased 1.34-fold the transport of RH across buccal epithelium, whereas an increase of 1.23- and 1.28-fold was reported in the presence of HP-β-CD and SBE-β-CD, respectively. Infrared spectroscopy (IR) was employed to investigate the interaction of permeation enhancers with the epithelial lipids of porcine buccal mucosa corroborating the permeation results. Finally, light microscopy was performed to assess the histological changes in the porcine epithelium. Formation of vacuoles, spongiosis and acantholysis linear detachment and destruction of the epithelium resulted from the presence of the permeation enhancers. The data suggest that all enhancers tested, and particularly TMC, increase the transport of RH across buccal epithelium.

Background: Laparoscopic sleeve gastrectomy is one of the most recent advances in the surgical treatment of morbid obesity. Extended follow-up studies of large cohorts are needed to establish the usefulness of the operation. The objectives of this study are to delineate the role of sleeve gastrectomy in weight loss and in comorbidities among obese patients. Methods: Patients who underwent laparoscopic sleeve gastrectomy in a single bariatric center were followed up for a 3-year period. Weight loss and status of several comorbidities were assessed at the 1st, 3rd, 6th, 12th, 18th, 24th, and 36th postoperative month. Results: Overall, after 3 years of follow-up of 88 patients, the mean body mass index (BMI) of the patients was 29.8 kg/m2 (SD ±6.1), the % total weight loss was 38.1 % (SD ±12.9), the % excess weight loss was 69.5 % (SD ±17.5), and the % estimated BMI loss was 81.4 % (SD ±22.3). These parameters changed significantly over the first year of follow-up (p

Summary En Face OCT and OCT Angiography are two innovative diagnostic modalities which were adapted for the diagnosis, therapeutic decision and observation of the evolution following conservative management in ocular oncology. En Face OCT is particulary useful for (1) The definition of the extend of serous retinal detachment and the documentation of its variations (2) The definition of the internal anatomical structure of unpigmented choroidal tumors (3) The definition of the limits of flat and diffused choroidal melanomas in order to define the target volume of the irradiation. Angio-OCT in ocular oncology is mainly used for the definition of retinal vascular lesions observed in radiation induced optic neuropathy and radiation induced maculopathy. This allows a better definition of the therapeutic strategies with anti-VEGF drugs in order to preserve visual function.

Purpose To study the outcome of patients treated for a choroidal hemangioma with proton beam irradiation following unsuccessful PDT and compare the therapeutic results with that of a control group that received proton therapy as a primary treatment. Methods Proton beam irradiation was applied to twelve cases of choroidal hemangioma that had been unsuccessfully treated with PDT (N of sessions: 1–5). Their functional results were compared to those of a control group of 48 cases treated only with proton therapy. The latter were matched (4 to 1) for the duration of symptoms before primary treatment, extent of retinal detachment as well as distance to the macula. Results The mean follow-up following proton beam irradiation therapy was 28 months [range: 6 months-5 years] in the PDT group and 41 months [range: 6 months-10 years] in the control group. In all patients, the retinal detachment and macular edema disappeared following proton therapy. In the study group, final visual acuity was ≤0.1 in 25%, 0.2–0.5 in 25% and ≥0.6% in 50% of cases. Visual acuity improved in 50%, remained stable in 42% and decreased in 8% of cases. In the control group, final visual acuity was ≤0.1 in 4%, 0.2-0.5 in 38% and ≥0.6 in 58% of cases. Visual acuity improved in 65%, remained stable in 29% and decreased in 6% of cases. Conclusions Proton beam irradiation is a valid therapeutic option after inconclusive results following PDT for choroidal hemangioma. Within the limits of this study, therapeutic results were slightly better for those patients that received proton therapy as a primary treatment.

The first direct arylation of 4-hydroxy-2-pyridones with aryl boronic acids under palladium acetate catalysis is described.