Stereochemical analysis of natural products. Approaches relying on the combination of NMR spectroscopy and computational methods

Abstract The stereochemical study of flexible stereogenic carbon chains, such as those of many novel natural products, is a particularly challenging task. Recent applications of our group on the so-called "J-based approach", a methodology relying on a detailed analysis of homonuclear (H-H) and heteronuclear (C-H) 2,3 J couplings, include the study of the sphinxolide family of antitumor macrolides, a group of molecules characterized by a flexible macrocyclic framework bearing a number of oxygenated and methylated undetermined stereocenters, and of ascaulitoxin, a nitrogen-containing phytotoxin with herbicidal activity produced by a phytopathogenic fungus. An extension of the original procedure, relying on a Hartree-Fock (HF) ab initio calculation of conformational equilibrium and an estimate of the Boltzmann averaged 2,3 JHH and 2,3 JCH couplings, has been applied to the stereochemical study of sapinofuranone A, where the conformational equilibrium among existing rotamers had initially led to controversial results. 13C NMR chemical shifts are additional useful parameters in the study of complex organic molecules. Along these lines, we have lately proposed the use of Hartree–Fock gauge including atomic orbitals (GIAO) calculated 13C NMR chemical shift values as a supporting tool for the validation of the structure of new natural products and the determination of the relative stereochemistry of diastereomeric flexible compounds that are characterized by multiple conformer equilibria

Apicidine, nuovi peptidi ciclici inibitori dell'istone deacetilasi (HDAC). Sintesi dei residui derivati dall'acido 2-amino 8-oxodecanoico (AODA)

Le Apicidine, una famiglia di tetrapeptidi ciclici di origine fungina, hanno mostrato una elevatissima attività  come inibitori reversibili di HDAC. Con l'obiettivo di sintetizzare le Apicidine e preparare analoghi semplificati che mantengano l'attività di inibitori di HDAC, abbiamo progettato una sintesi generale e multivariabile di derivati dell'acido 2-ammino-8-oxodecanoico

Synthesis, structural aspects and cytotoxicity of the natural cyclopeptides yunnanins A, C and phakellistatins 1, 10

Yunnanins A and C, two cyclic heptapeptides occurring in the roots of Stellaria yunnanensis, and phakellistatins 1 and 10, a hepta- and an octacyclopeptide first isolated from marine sponges of the genus Phakellia, were efficiently synthesized using a combination of solid and solution-phase techniques. Structural analysis on the synthetic members of the yunnanin series showed that the synthetic sample of yunnanin A exhibited a configurational pattern at the Pro peptide linkages identical to the natural product (trans-Pro3, trans-Pro5), while yunnanin C was obtained as a complex mixture of geometric/conformational isomers; the major isomer (trans-Pro3) was indistinguishable from the natural cyclopeptide and co-occurred along with lower amounts of a mixture (1:1 ratio) of two different rotamers, both displaying cis geometry at the Pro3 linkage. In the phakellistatin series, the synthetic phakellistatin 1 (determined as cis-Pro1, cis-Pro3, cis-Pro5) was identical to the natural one, while two different isomeric products of phakellistatin 10 could be obtained: a major one (trans-Pro1, trans-Pro4, trans-Pro6) showing spectral properties superimposable with the natural metabolite, and a minor geometric isomer of the natural cyclopeptide. Interestingly, the synthetic cyclopeptides, although found to be chemically identical with their natural counterparts, did not display the same biological properties (in vitro cytotoxicity against a panel of cancer cell lines), leaving presently open the question whether or not the potent bioactivity reported in the literature should really be attributed to these natural cyclic peptides. q 2003 Elsevier Ltd. All rights reserved

Synthesis of kainoids via a highly stereoselective hydroformylation of kainic acid.

An efficient prepn. of a series of secondary amines, structurally related to the kainic acid scaffold, is described.  Naturally occurring (-)-α-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity.  The stereochem. of the product was investigated through the ROESY and HETLOC spectra of the corresponding 2,4-dinitrophenylhydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group.  The aldehyde was used as a platform to prep. amines by reductive amination in ionic liqs

Effects of petrosaspongiolide M, a novel phospholipase A2 inhibitor, on acute and chronic inflammation

ABSTRACT The marine product petrosaspongiolide M is a novel inhibitor of phospholipase A 2 (PLA 2 ), showing selectivity for secretory PLA 2 versus cytosolic PLA 2 , with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA 2 (group III) and had no effect on group I enzymes (Naja naja and porcine pancreatic PLA 2 ). Inhibition of PLA 2 was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This marine metabolite (0.01-1.0 mol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E 2 , leukotriene B 4 , and tumor necrosis factor-␣ in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B 4 levels in serum and PGE 2 levels in paw homogenates. In contrast with indomethacin, this marine compound did not reduce PGE 2 levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA 2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Haliclamide, a Novel Cyclic Metabolite from the Vanuatu Marine Sponge Haliclona sp.

A new cyclic metabolite, named haliclamide (1), has been isolated from the Vanuatu marine sponge Haliclona sp. Its structure was determined from 1D and 2D NMR studies and mass spectral data. Haliclamide (1) represents a new 16-membered cyclic depsipeptide containing, along with a N-methylphenylalanine, two residues never isolated from natural sources: 5-hydroxy-octanoic acid (HOA) and 6-amino-7-hydroxy-2-methylheptanoic acid (AHMA). Haliclamide (1) exhibited cytotoxicity against the NSCLC-N6 human bronchopulmonary non-small-cell-lung carcinoma cell lines with an IC50 value of 4.0 mug/mL

Stereochemical assignment at C-24 and C-25 of marine 24-ethyl-26-hydroxy steroids through comparison with synthetic (24S,25S)-, (24S,25R)-, (24R,25R)-, and (24R,25S)-models

The four diastereoisomers of cyclostigmastanol I and their E-22-unsatd. derivs. were prepd. Anal. of 1H and 13C NMR spectra of the synthetic model compds. and of their α-methoxy-α-(trifluoromethyl)phenylacetates provided data suitable for the assignment of configuration at C-24 and C-25 in 24-ethyl-26-hydroxysteroids. The stereochem. (24S,25S) has been assigned to 24-ethyl-5β-cholestane-3α,4α,21,26-tetrol 3,21-disulfate (II), recently isolated from the marine ophiuroid Ophiolepis supereba