Synthesis of the monomeric counterpart of Marinomycin A and B.

The synthesis of polyketide natural products has been a captivating pursuit in organic chemistry, with a particular focus on selectively introducing 1,3-polyol units. Among these natural products, Marinomycins A-D have garnered substantial interest due to their exceptional structural features and potent cytotoxicity. In this paper, we present a novel approach for synthesising the monomeric counterparts of Marinomycin A and B. Our method employs a previously established iterative cycle in conjunction with a standardised polyketide building block. Through this strategy, we showcase a promising pathway towards total and partial syntheses of these intriguing natural products.

Safety and performance assessment of hyaluronic acid-based vitreous substitutes in patients with phthisis bulbi.

PURPOSE: To assess the safety and performance of hyaluronic acid-based vitreous substitutes in phthitic eyes. METHODS: In this retrospective interventional study a total of 21 eyes from 21 patients with phthisis bulbi were treated at the Eye Clinic Sulzbach between August 2011 and June 2021. Patients who underwent a 23G pars plana vitrectomy received a vitreous substitute composed of (I) a non-crosslinked hyaluronic acid (Healon GV), (II) a crosslinked hyaluronic acid-based hydrogel (UVHA), or (III) silicone oil (SO-5000). Main outcome measures were the intraocular pressure (IOP), the visual acuity and the structural integrity of the retina and choroid assessed by optical coherence tomography. RESULTS: An increase in IOP ≥ 5 mmHg was achieved with SO-5000 in 5/8 eyes (6/10 interventions, 60.0%) for 36.4 ± 39.5 days, with Healon GV in 4/8 eyes (7/11 interventions, 63.6%) for 82.6 ± 92.5 days and with UVHA in 4/5 eyes (5/6 interventions, 83.3%) for 93.6 ± 92.5 days. Visual acuity increased in 5/21 eyes (23.8%), remained constant in 12/21 eyes (57.1%) and decreased in 4/21 eyes (19.0%). No enucleations were required during the mean follow-up time of 192 ± 182 days. The OCT images indicated the preservation of retinal structures, while choroidal folds were only diminished in UVHA eyes. CONCLUSIONS: Hyaluronic acid-based hydrogels are biocompatible vitreous substitutes in humans and can increase and stabilize IOP in patients with phthisis bulbi for about 3 months.

Translation of hyaluronic acid-based vitreous substitutes towards current regulations for medical devices.

PURPOSE: Hydrogel-based vitreous substitutes have the potential to overcome the limitations of current clinically used endotamponades. With the goal of entering clinical trials, the present study aimed to (I) transfer the material synthesis of hyaluronic acid-based hydrogels into a routine, pharmaceutical-appropriate production and (II) evaluate the properties of the vitreous substitutes in terms of the current regulations for medical devices (MDR/ISO standards). METHODS: The multistep manufacturing process of the vitreous substitutes, including the modification of hyaluronic acid with glycidyl methacrylate, photocopolymerization with N-vinylpyrrolidone, and successive hydrogel purification, was developed under laboratory conditions, characterized using 1 H-NMR, FT-IR and UV/Vis spectroscopies and HPLC, and transferred towards a pharmaceutical production environment considering GMP standards. The optical and viscoelastic characteristics of the hyaluronic acid-based hydrogels were compared with those of extracted human vitreous and silicone oil. The effect of the hydrogels on the metabolic activity, proliferation and apoptosis of fibroblast (MRC-5, BJ, L929), retinal pigment epithelial (ARPE-19, hiPSC-derived RPE) and photoreceptor cells (661W) was studied as well as their mucosal tolerance via a HET-CAM assay. RESULTS: Hyaluronic acid-based hydrogels having a suitable purity, sterility, high transparency (>90%), appropriate refractive index (1.3365) and viscoelasticity (G' > G″) were prepared in a standardized manner under controlled process conditions. The metabolic activity, proliferation and apoptosis of various cell types as well as egg choroid were unaffected by the hyaluronic acid-based vitreous substitutes, demonstrating their biocompatibility. CONCLUSIONS: The present study demonstrates the successful transferability of the crucial synthesis steps of hyaluronic acid-based hydrogels into a routine, GMP-compliant production process while achieving the optical and viscoelastic properties, biocompatibility and purity required for their clinical use as vitreous substitutes.

Hydrofluoric Acid and Other Impurities in Toxic Perfluorooctane Batches.

PURPOSE: The complications with cytotoxic perfluorooctane (PFO) batches reported in 2015 were attributed to reactive underfluorinated impurities whose chemical identity and behavior still need to be clarified. MATERIAL AND METHODS: We analyzed original packaged samples of Ala®octa batches involved in several reported cases of retinal toxicity. (A) The impurity profile was determined. (B) pH and fluoride ion content were measured. (C) Extraction with olive oil was performed to investigate differences in lipophilia among perfluorinated liquid (PFCL) as a measure for penetration of lipophilic cell membranes followed by measurements (A) and (B). RESULTS: (A) The detected impurities can be divided into: (1) reactive underfluorinated compounds and their degradation products including hydrogen fluoride (HF), (2) nonreactive underfluorinated compounds, (3) surface active compounds, (4) nonreactive fluorinated compounds, and (5) leachables from primary packaging components. The highest acute toxic potential is associated with the impurities of group (1). (B) HF was detected as a degradation product of reactive underfluorinated impurities by relying on the pH values and fluoride ion content of the water extracts. (C) Lipophilic impurities dissolved in PFO migrate into lipophilic extraction medium. In particular, HF is rapidly transferred in this way. CONCLUSIONS: HF as degradation product of unstable or reactive underfluorinated contaminants seems of particular importance triggering the acute toxicity of affected PFO. Contamination related toxicity and unwanted side effects can only be reliably excluded via analytical controlled multistage, high-purification processes. TRANSLATIONAL RELEVANCE: In Ala®octa batches different impurities show retinal toxicity. HF seems of particular importance of the acute toxicity of PFO.

How to Ward Off Retinal Toxicity of Perfluorooctane and Other Perfluorocarbon Liquids?

Purpose: Reactive and underfluorinated impurities are acknowledged as a source of cytotoxicity of perfluorocarbon liquids (PFCLs) used as blood substitutes. To determine whether this is also a relevant factor in retinal toxicity, we analyzed eight PFO batches associated with adverse ocular events. Methods: (A) The amount of reactive and underflurinated impurities was analyzed by fluoride-selective potentiometry and expressed as H-value. (B) Cytotoxicity of these batches was determined by an ISO 10993-5-compliant extractive test and compared to published data generated with a direct-contact method. (C) A toxic PFO batch (061014) was purified to remove reactive and underfluorinated impurities. (A) and (B) -measurements were repeated after that. (D) The dose dependence of the H-value and cytotoxicity was determined in a dilution experiment. Results: (A) The batches revealed H-values ranging from 1.400 ppm to 4.500 ppm. (B) All batches induced cell growth inhibition; seven must be classified as cytotoxic. Findings from ISO-conform extractive and direct-contact methods showed no difference. (C) After all reactive and underfluorinated impurities in batch 061014 were removed, the H-value dropped to <10 ppm and cytotoxicity disappeared. (D) Cytotoxicity increases gradually as the H-value rises. Conclusions: The clinical relevance of the H-value as a safety parameter for PFO endotamponades could be proven. The H-value is a measure for reactive and underfluorinated impurities that cause toxicity of PFCLs and should be incorporated in each endotamponade specification with a limit of 10 ppm to prove the effectiveness of the ultra-purification required and ensure a safe product. Despite the fact that an (ISO)-standard literally is a "standard" only, which cannot cover all imaginable possibilities, the incorporation of the H-value determination into the relevant ISO standard has been initiated. If a thorough risk assessment results in risks that cannot be detected and/or managed by the effective standard, additional investigations have to be performed.

Synthesis of a Model Tetracyclic Core Structure of Calyciphylline B-Type Alkaloids.

Herein, we report the enantioselective synthesis of a functionalized aza-octahydropentalene and its elaboration to a model tetracyclic core structure of calyciphylline B-type alkaloids.

Concise and stereocontrolled synthesis of the tetracyclic core of daphniglaucin C.

The tetracyclic core of daphniglaucin C was prepared from the known 4-keto-N-Boc methyl-l-prolinate in 15 steps with a cumulative yield of 14.7%. The key steps toward this core motif feature a reductive double bond transposition from an unactivated tertiary allylic alcohol, a Pd-catalyzed Stille coupling, and Dieckmann cyclizations.

Rugulactone and its analogues exert antibacterial effects through multiple mechanisms including inhibition of thiamine biosynthesis.

Rugulactone is a dihydro-α-pyrone isolated from the plant Cryptocarya rugulosa in 2009. It has been reported to display IkB kinase (IKK) inhibitory activity, as well as antibiotic activity in several strains of pathogenic bacteria. However, its biological targets and mode of action in bacteria have not yet been explored. Here we present enantioselective syntheses of rugulactone and of some corresponding activity-based protein profiling (ABPP) probes. We found that the ABPP probes in this study are more potent than rugulactone against Staphyloccocus aureus NCTC 8325, S. aureus Mu50, Listeria welshimeri SLCC 5334 and Listeria monocytogenes EGD-e, and that molecules of this class probably exert their antibacterial effect through a combination of targets. These targets include covalent inhibition of 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMPP) kinase (ThiD), which is an essential component of the thiamine biosynthesis pathway in bacteria. This represents the first example of a small-molecule inhibitor of ThiD.

Total synthesis of polyrhacitides A and B by use of an iterative strategy for the stereoselective synthesis of 1,3-polyol arrays.

The first total syntheses of polyrhacitides A and B, secondary metabolites from Chinese medicinal ants, were accomplished via an iterative approach to the 1,3-polyol motif. For the construction of all stereogenic centers, the catalytic asymmetric Overman esterification was utilized.

Direct carbocyclization of aldehydes with alkynes: combining gold catalysis with aminocatalysis.

A combination of gold(I) complexes and amine bases catalyzes the 5-exo-dig cyclization of formyl alkynes. This direct alpha-functionalization of aldehydes with unactivated alkynes does not involve the use of preformed enol equivalents.

Synthesis of stable 2H-pyran-5-carboxylates via a catalyzed propargyl-Claisen rearrangement/oxa-6pi electrocyclization strategy.

[reaction: see text] The application of easily accessed propargyl vinyl ethers for the synthesis of monocyclic 2H-pyrans was achieved. Under the reaction conditions, highly substituted heterocycles were obtained in moderate to excellent yields. The one-pot sequence proceeds via a Ag(I)-catalyzed propargyl-Claisen rearrangement, followed by a base-catalyzed isomerization, and 6pi-oxaelectrocyclization, leading to the formation of stable 2H-pyrans.