Obesity-related leptin resistance manifests in loss of leptin’s ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid ...system, and CB1 receptor (CB1R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB1R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB1R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB1R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.
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► Peripheral CB1 receptor inverse agonist reduces obesity and its metabolic sequelae ► Peripheral CB1 blockade reduces food intake and body weight via endogenous leptin ► CB1 blockade restores leptin sensitivity by reversing hyperleptinemia of obesity ► Hyperleptinemia is reversed via reduced secretion and increased clearance of leptin
We report a novel synthesis of phenanthridinones from N-methoxybenzamides using an oxidative C–H amidation reaction at room temperature in open air with modest to excellent yields. This method ...demonstrated unprecedented substrate scope. In particular, it solved the long-standing challenge in the synthesis of phenanthridinones with sterically demanding substitutions.
Extension of the asymmetric Pictet–Spengler reaction to bulkier Nb‐alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo3.3.1nonane core of bioactive C‐19 ...methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C‐19 methyl function in either the α‐ or β‐configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A‐C) 1–3, talcarpine 4, N(4)‐methyl‐N(4),21‐secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9.
Indole synthesis: We have extended the asymmetric Pictet–Spengler reaction to bulkier tryptophan derivatives. This resulted in an improved stereospecific access to the key bicyclo3.3.1nonane core of bioactive C‐19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction.
Proteases are enzymes that catalyse the breaking of specific peptide bonds in proteins and polypeptides. They are heavily involved in many normal biological processes as well as in diseases, ...including cancer, stroke and infection. In fact, proteolytic activity is sometimes used as a marker for some cancer types. Here we present luminescent quantum dot (QD) bioconjugates designed to detect proteolytic activity by fluorescence resonance energy transfer. To achieve this, we developed a modular peptide structure which allowed us to attach dye-labelled substrates for the proteases caspase-1, thrombin, collagenase and chymotrypsin to the QD surface. The fluorescence resonance energy transfer efficiency within these nanoassemblies is easily controlled, and proteolytic assays were carried out under both excess enzyme and excess substrate conditions. These assays provide quantitative data including enzymatic velocity, Michaelis-Menten kinetic parameters, and mechanisms of enzymatic inhibition. We also screened a number of inhibitory compounds against the QD-thrombin conjugate. This technology is not limited to sensing proteases, but may be amenable to monitoring other enzymatic modifications.
A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53−MDM2 protein−protein interaction is reported. The most potent compound 1d binds to MDM2 ...protein with a K i value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16−27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein−protein interaction, which remains a very challenging area in chemical biology and drug design.
The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were ...based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro2,3-cazocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro2,3-cazocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).
The unique properties provided by hybrid semiconductor quantum dot (QD) bioconjugates continue to stimulate interest for many applications ranging from biosensing to energy harvesting. Understanding ...both the structure and function of these composite materials is an important component in their development. Here, we compare the architecture that results from using two common self-assembly chemistries to attach DNA to QDs. DNA modified to display either a terminal biotin or an oligohistidine peptidyl sequence was assembled to streptavidin/amphiphilic polymer- or PEG-functionalized QDs, respectively. A series of complementary acceptor dye-labeled DNA were hybridized to different positions on the DNA in each QD configuration and the separation distances between the QD donor and each dye-acceptor probed with Förster resonance energy transfer (FRET). The polyhistidine self-assembly yielded QD−DNA bioconjugates where predicted and experimental separation distances matched reasonably well. Although displaying efficient FRET, data from QD−DNA bioconjugates assembled using biotin−streptavidin chemistry did not match any predicted separation distances. Modeling based upon known QD and DNA structures along with the linkage chemistry and FRET-derived distances was used to simulate each QD−DNA structure and provide insight into the underlying architecture. Although displaying some rotational freedom, the DNA modified with the polyhistidine assembles to the QD with its structure extended out from the QD−PEG surface as predicted. In contrast, the random orientation of streptavidin on the QD surface resulted in DNA with a wide variety of possible orientations relative to the QD which cannot be controlled during assembly. These results suggest that if a particular QD biocomposite structure is desired, for example, random versus oriented, the type of bioconjugation chemistry utilized will be a key influencing factor.
All five: The first total synthesis of the C2‐symmetric indole alkaloid 1 involved a late‐stage thallium(III) acetate‐mediated intermolecular oxidative coupling to construct the C9C9′ bond with ...complete regio‐ and stereocontrol. The formation of a single atropodiastereomer in this critical step arises from internal asymmetric induction. The first total synthesis of four other monomeric sarpagine indole alkaloids is also described.
The sequential use of a hypervalent iodine reagent leads to the one-pot synthesis of 2-bromo/chloro-phenanthridinones via an amidation of arenes followed by a regioselective halogenation reaction. ...These consecutive C-H functionalization reactions can be used efficiently to construct 2-substituted-phenanthridinones at room temperature with good to high yields. Application of the current method is highlighted by the concise synthesis of the natural product PJ34.
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