The first total synthesis of muricadienin, the unsaturated putative precursor in the biosynthesis of trans- and cis-solamin is described. Key steps in the synthesis are a chemoselective hydroboration, a Z-selective Wittig reaction, and a Fries rearrangement for introducing the terminal ?-substituted butenolide. Thus, muricadienin can be synthesized in 11 steps from commercially available starting materials in 42% overall yield.
The heronapyrroles A-C have first been isolated from a marine-derived Streptomyces sp. (CMB-0423) in 2010. Structurally, these natural products feature an unusual nitropyrrole system to which a partially oxidized farnesyl chain is attached. The varying degree of oxidation of the sesquiterpenyl subunit in heronapyrroles A-C provoked the hypothesis that there might exist other hitherto unidentified metabolites. On biosynthetic grounds a mono-tetrahydrofuran-diol named heronapyrrole D appeared a possible candidate. We here describe a short asymmetric synthesis of heronapyrrole D, its detection in cultivations of CMB-0423 and finally the evaluation of its antibacterial activity. We thus demonstrate that biosynthetic considerations and the joint effort of synthetic and natural product chemists can result in the identification of new members of a rare class of natural products.
A new method to accomplish glycol cleavage to carboxylic (di)acids in one step using catalytic amounts of tetrapropylammonium perruthenate (TPAP) together with N-methylmorpholine N-Oxide (NMO) as the stoichiometric oxidant is presented. In addition to regenerating the active catalyst, the N-oxide stabilizes intermediary carbonyl hydrates and thereby shifts a crucial equilibrium. The mild oxidation protocol is applicable to a broad range of substrates providing the respective acids, diacids, or keto acids in high yields.
The synthesis of novel ?-functionalized derivatives of the clinically used photosensitizer Temoporfin has been achieved by nucleophilic addition reactions to a corresponding diketo chlorin. The ?-substituted dihydroxychlorin products exhibit a strong absorption in the red spectral region, a high singlet oxygen quantum yield, and were found to be highly effective in in vitro assays against HT-29 tumor cells.
We present a simple, mild, and highly effective method for the direct conversion of primary alcohols to carboxylic acids. TPAP serves as the catalyst, and NMO·H(2)O plays a dual role, acting as the co-oxidant and as a reagent for aldehyde hydrate stabilization. This previously unknown stabilizing effect of geminal diols by N-oxides is the key for the efficiency of the overall transformation.
This study examined the effects of reduced plantar cutaneous afferent feedback on predictive and feedback adaptive locomotor adjustments in dynamic stability during perturbed walking. Twenty-two matched participants divided between an experimental-group and a control-group performed a gait protocol, which included surface alterations to one covered exchangeable gangway-element (hard/soft). In the experimental-group, cutaneous sensation in both foot soles was reduced to the level of sensory peripheral neuropathy by means of intradermal injections of an anaesthetic solution, without affecting foot proprioception or muscles. The gait protocol consisted of baseline trials on a uniformly hard surface and an adaptation phase consisting of nineteen trials incorporating a soft gangway-element, interspersed with three trials using the hard surface-element (2nd, 8th and 19th). Dynamic stability was assessed by quantifying the margin of stability (MS), which was calculated as the difference between the base of support (BS) and the extrapolated centre of mass (CM). The horizontal velocity of the CM and its vertical projection in the anterior-posterior direction and the eigenfrequency of an inverted pendulum determine the extrapolated-CM. Both groups increased the BS at the recovery step in response to the first unexpected perturbation. These feedback corrections were used more extensively in the experimental-group, which led to a higher MS compared to the control-group, i.e. a more stable body-position. In the adaptation phase the MS returned to baseline similarly in both groups. In the trial on the hard surface directly after the first perturbation, both groups increased the MS at touchdown of the disturbed leg compared to baseline trials, indicating rapid predictive adjustments irrespective of plantar cutaneous input. Our findings demonstrate that the locomotor adaptational potential does not decrease due to the loss of plantar sensation.
Portal hypertension in cirrhosis depends on increased intrahepatic vascular resistance, which is explained by fibrosis and intrahepatic hyperresponsiveness to vasoconstrictors. Both are caused by activation and proliferation of hepatic stellate cells (HSCs). Portal hypertension of cirrhotic rats can be reduced by the multikinase inhibitor sorafenib, due to a reduction of intrahepatic vascular resistance. Therefore, the hepatic effects of sorafenib require further understanding. Here, we investigated hepatic and HSC-specific sorafenib effects in cirrhotic rats. Animal models of bile duct ligation-induced secondary biliary cirrhosis in rats were studied. The rats were treated with sorafenib (60?mg/kg/day) for 1 week, starting after established cirrhosis. Histological evaluation was carried out using hemalaun and eosin (HE) staining. Apoptosis was studied by PARP cleavage, colorimetric caspase-3 assay, and electrophoretic DNA detection. HSC activation was studied by hepatic Sirius red and immunohistochemical ?SMA (?-smooth muscle actin) staining, and by in vitro experiments with culture-activated primary HSCs. Biochemical serum parameters suggested the occurrence of sorafenib-induced liver damage. HE staining revealed histological changes in livers of sham-operated and bile duct-ligated (BDL) rats in response to sorafenib, which were different in both groups. In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic ?SMA and procollagen-1? mRNA expression. As shown by immunohistochemical staining, perisinusoidal ?SMA expression was reduced by sorafenib in BDL rats. This was associated with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care.
Plantar ulcers are a common and severe complication of the diabetic neuropathic foot. Increased plantar pressures while walking are associated to incidence of plantar ulcer formation in diabetes. There is a strong correlation between the increase in plantar pressures and the severity of peripheral neuropathy. One consequence of peripheral sensory neuropathy is insensitive skin. The influence of reduced plantar sensitivity on changes in plantar pressure distribution is not well understood. The purpose of this study was to identify possible causal dependences between reduced plantar cutaneous sensation and plantar pressure distribution during gait.
The first synthesis of (-)-heronapyrrole C, the enantiomer of a unique farnesylated 2-nitropyrrole natural product is described. With none of the chiral centers of heronapyrrole C originally assigned, we proposed the most likely natural configuration on the basis of a putative biosynthetic pathway. The key step of the synthesis is a biomimetic polyepoxide cyclization cascade to establish the bis-THF moiety. Thus, (-)-heronapyrrole C is synthesized in eight steps from commercially available starting materials.
Peripheral neuropathy is the most common long-term complication in diabetes and is involved in changes in diabetic gait and posture. The regression of nerve function leads to various deficits in the sensory and motor systems, impairing afferent and efferent pathways in the lower extremities. This study aimed to examine how reduced plantar-afferent feedback impacts the gait pattern. Cutaneous sensation in the soles of both feet was experimentally reduced by means of intradermal injections of an anaesthetic solution, without affecting foot proprioception or muscles. Ten subjects performed level walking at a controlled velocity before and after plantar anaesthesia. Muscle activity of five leg-muscles, co-contraction ratios for the knee and ankle joint, ground reaction forces (GRF), spatiotemporal characteristics, joint angles and moments of the hip, knee and ankle were analysed. The intervention significantly lowered plantar sensation, reducing it to the level of sensory neuropathy. Spatiotemporal gait characteristics remained unchanged. The ankle joint was more dorsiflexed which coincided with increased tibialis anterior and decreased gastrocnemius medialis muscle activity during foot flat to mid-stance. In addition, the knee joint was more flexed accompanied by increased biceps femoris activity and higher internal knee-extension moment. With regard to gait dynamics, a delay of the first peak of the vertical GRF was observed. Increased soleus and tibialis anterior muscle activity were found during the end of stance. Short-term loss of plantar sensation affects lower-limb kinematics and gait dynamics, particularly during the first half of stance, and contributes to modified muscle-activation patterns during locomotion.
The synthesis of 2-nitro-4-oligoprenyl substituted pyrrole derivatives relevant to the heronapyrroles and related natural products was investigated. Among numerous approaches nitration of a 3-farnesyl-substituted unprotected pyrrole using AcONO2 gave best results, albeit still with unsatisfactory yield and regioselectivity. Therefore, the synthesis of (-)-heronapyrrole C acid, an analogue of the naturally occurring antibiotic heronapyrrole C, carrying a bioisosteric carboxylate in place of the nitro group was examined. In lieu of the unsatisfactory nitration a regioselective acylation with Cl3CCOCl was carried out (> 8:1 regioselectivity; in contrast to the 1:1.3 ratio for the nitration). The trichloromethyl ketone was converted to the desired acid in a haloform reaction at the final stage of the synthesis. Further key steps of the analogue synthesis involved a position- and stereoselective Corey-Noe-Lin-dihydroxylation and an organocatalytic double Shi-epoxidation. A biomimetic polyepoxide cyclization cascade established the bis-THF backbone. Thus, (-)-heronapyrrole C acid was synthesized in 8 steps (14.5% overall yield) from commercially available starting materials.
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