Studies directed to the total synthesis of biologically active natural products

The total synthesis of biologically active, naturally occurring substances is an ambitious task. Fascinating new methods have been developed for the synthesis of natural products. We discuss the following accomplishments: (1) The short and convergent synthesis of 4,1-Bisdeoxydaunamycinone by Claisen/Diels-Alder sequence. (2) The regiochemical studies on the Diels-Alder reaction of electron-rich dienes and activated dienophiles, and the effort toward the aza-tricyclic moiety of atisine-type alkaloids. (3) The formation of bicyclic and monocyclic intermediates via silyl radical induced cyclizations, and the first chemoselective studies on silicon radicals

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat

Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency and α-helicity and reveal interactions vital for cAMP signaling in vitro

Glucagon-like peptide-1 (GE P-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide alpha-conotoxin p114a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe' into a hydrophobic pocket on the GLP-1R

Translational diffusion of cyclic peptides measured using pulsed-field gradient NMR

Cyclic peptides are increasingly being recognized as valuable templates for drug discovery or design. To facilitate efforts in the structural characterization of cyclic peptides, we explore the use of pulse-field gradient experiments as a convenient and noninvasive approach for characterizing their diffusion properties in solution. We present diffusion coefficient measurements of five cyclic peptides, including dichC, SFTI-1, cVc1.1, kB1, and kB2. These peptides range in size from six to 29 amino acids and have various therapeutically interesting activities. We explore the use of internal standards, such as dioxane and acetonitrile, to evaluate the hydrodynamic radius from the diffusion coefficient, and show that 2,2-dimethyl-2-silapentane-5-sulfonic acid, a commonly used chemical shift reference, can be used as an internal standard to avoid spectral overlap issues and simplify data analysis. The experimentally measured hydrodynamic radii correlate with increasing molecular weight and in silico predictions. We further applied diffusion measurements to characterize the self-association of kB2 and showed that it forms oligomers in a concentration-dependent manner, which may be relevant to its mechanism of action. Diffusion coefficient measurements appear to have broad utility in cyclic peptide structural biology, allowing for the rapid characterization of their molecular shape in solution

Pengaruh Harga Terhadap Peningkatan Penjualan Produk Semen Tiga Roda Pada PT. Robcaga Beo Kabupaten Kepulauan Talaud

The development in business world these days is market by the competition between the business company is getting fierce. Especially in managing the company business unit. It is shown by the appearance of a company that offer a good quality product with a compete price on the market. To handle the fierce competition on the market then one from so many effort that the company do is by apply the strategic price. Which on the way of applying that strategi the company try to set a price that can be compete in the market so the increase sale of the product become maximum. With right price and controlled will result the domino effect to a company to build long term relationship with costumer so it can increase the sales volume. This research is a descriptive quantitative research by using the correlation approach and simple regression. To see relation between variable and to measure the impact to the variable itself. So the purpose of this research is to know how far the price effect and to the increase of PT. ROBCAGA in Talaud. According to the sesult of the research, can be shown as following: price has a correlation and significant determination effort to the increase sale of PT. ROBCAGA Talaud. According to the data analysis, coefficient value moment r = 0,685. That show there is a positive relation, and can be categorize as high and strong, also price coefficient determination to the increase sale is by 46,5% and 53,5% by the rest of it depends on the unknown factors that not been analyze in this research

Comparative α-Helicity of Cyclic Pentapeptides in Water

Helix-constrained polypeptides have attracted great interest for modulating protein-protein interactions (PPI). It is not known which are the most effective helix-inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X-1-X-5) were compared here, using circular dichroism and 2D NMR spectroscopy, for a-helix induction in simple model pentapeptides, Ac-cyclo(1,5)-[X-1-Ala-Ala-Ala-X-5]-NH2, in water. In this very stringent test of helix induction, a Lys1 -> Asp5 lactam linker conferred greatest alpha-helicity, hydrocarbon and triazole linkers induced a mix of alpha- and 3(10)-helicity, while thio-and dithioether linkers produced less helicity. The lactam-linked cyclic pentapeptide was also the most effective a-helix nucleator attached to a 13-residue model peptide

Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists

Type 2 diabetes mellitus (T2DM) results from compromised pancreatic beta-cell function, reduced insulin production, and lowered insulin sensitivity in target organs resulting in hyperglycemia. The GLP-1 hormone has two biologically active forms, GLP-1-(7-37) and GLP-1-(7-36)amide, which are equipotent at the glucagon-like peptide-1 receptor (GLP-1R). These peptides are central both to normal glucose metabolism and dysregulation in T2DM. Several structurally modified GLP-1 analogues are now approved drugs, and a number of other analogues are in clinical trials. None of these compounds is orally bioavailable and all require parenteral delivery. Recently, a number of smaller peptidomimetics containing 11-12 natural and unnatural amino acids have been identified that have similar insulin regulating profiles as GLP-1. The alpha-conotoxins are a class of disulfide rich peptide venoms isolated from cone snails, and are known for their highly constrained structures and resistance to enzymatic degradation. In this study, we examined whether 11-residue peptidomimetics incorporated into alpha-conotoxin scaffolds, forming monocyclic or bicyclic compounds constrained by disulfide bonds and/or backbone cyclization, could activate the GLP-1 receptor (GLP-1R). Several compounds showed potent (nanomolar) agonist activity at GLP-1R, as evaluated via cAMP signaling. In addition, HPLC retention times and in silica calculations suggested that mono- and bicyclic compounds had more favorable n-octanol/water partition coefficients according to the virtual partition coefficient model (vLogP), while maintaining a smaller radius of gyration compared to corresponding uncyclized peptidomimetics. Our findings suggest that cyclic peptidomimetics provide a potential avenue for future design of potent, compact ligands targeting GLP-1R and possessing improved physicochemical properties. (C) 2015 Elsevier Masson SAS. All rights reserved

Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling

Glucagon-like peptide (GLP-1) is an endogenous hormone that induces insulin secretion from pancreatic islets and modified forms are used to treat diabetes mellitus type 2. Understanding how GLP-1 interacts with its receptor (GLP-1R) can potentially lead to more effective drugs. Modeling and NMR studies of the N-terminus of GLP-1 suggest a β-turn between residues Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. N-terminal turn constraints attenuated binding affinity and activity (compounds 1–8). Lys-Asp (i, i+4) crosslinks in the middle and at the C-terminus increased alpha helicity and cAMP stimulation without much effect on binding affinity or beta-arrestin 2 recruitment (compounds 9–18). Strategic positioning of helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased peptide helicity and produced ten-fold higher cAMP potency (compounds 19–28) over GLP-1(7–37)-NH. The most potent cAMP activator (compound 23) was also the most potent inducer of insulin secretion

Studies directed to the total synthesis of biologically active natural products

The total synthesis of biologically active, naturally occurring substances is an ambitious task. Fascinating new methods have been developed for the synthesis of natural products. We discuss the following accomplishments: (1) The short and convergent synthesis of 4,1-Bisdeoxydaunamycinone by Claisen/Diels-Alder sequence. (2) The regiochemical studies on the Diels-Alder reaction of electron-rich dienes and activated dienophiles, and the effort toward the aza-tricyclic moiety of atisine-type alkaloids. (3) The formation of bicyclic and monocyclic intermediates via silyl radical induced cyclizations, and the first chemoselective studies on silicon radicals.</p