AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Design, synthesis and biological evaluation of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives as antiglioma agents

 drugs, spectroscopy, SYNTHESIS  Comments Off on Design, synthesis and biological evaluation of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives as antiglioma agents
Feb 082018
 

Med. Chem. Commun., 2018, Advance Article
DOI: 10.1039/C7MD00551B, Research Article
Yi-Bin Li, Wen Hou, Hui Lin, Ping-Hua Sun, Jing Lin, Wei-Min Chen
Two series of 5-hydroxy-2-methyl-4H-pyran-4-one derivatives were synthesized and their antiglioma activities were evaluated.

Design, synthesis and biological evaluation of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives as antiglioma agents

Author affiliations

Abstract

D-2-Hydroxyglutarate (D-2HG) is frequently found in human brain cancers. Approximately 50–80% of grade II glioma patients have a high level of D-2HG production, which can lead to cancer initiation. In this study, a series of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives were designed and synthesized as antiglioma agents, and their related structure–activity relationships are discussed. Among these novel compounds, 4a exhibited promising anti-proliferative activity against glioma HT1080 cells and U87 cells with an IC50 of 1.43 μM and 4.6 μM, respectively. Further studies found that the most active compound (4a) shows an 86.3% inhibitory rate against the intracellular production of D-2HG at 1 μM, and dramatic inhibitory effects, even at 1 μM on the colony formation and migration of U87 and HT1080 cells.

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6,6′-((4-(Benzyloxy)phenyl)methylene)bis(5-hydroxy-2-methyl-4H-pyran-4- one) (4a) The reaction was performed according to the general procedure C, using 1 (1.00 g, 7.90 mmol) and 4-(benzyloxy)benzaldehyde (0.84 g, 3.95 mmol).2 The crude product was recrystallized from isopropanol affording a white powder 4a (1.53 g, 87%): mp 261.4-262.1oC; 1HNMR (300 MHz, DMSO-d6)  2.22 (s, 6H, CH3), 5.08 (s, 3H, OCH2- Ph), 5.96 (s, 1H, CH-Ar), 6.25 (s, 2H, C=CH), , 7.01 (d, J = 9.0 Hz, 2H, Ar-H3’/H5’), 7.22 (d, J = 9.0 Hz, 2H, Ar-H2’/H6’), 7.31-7.45 (m, 5H, Ph-H); 13CNMR (75 MHz, DMSO-d6)  173.95, 165.08, 158.12, 151.20, 147.68, 142.19, 140.77, 137.42, 129.87, 128.91, 128.16, 127.69, 115.46, 114.97, 111.74, 69.69, 19.63; ESI-MS m/z: 447.1 [M+H]+ ; ESI-HRMS m/z: 447.1438 [M+H]+ , calcd for C26H23O7 447.1438.
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A deeper shade of green: inspiring sustainable drug manufacturing

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Jan 062017
 

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

 

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A deeper shade of green: inspiring sustainable drug manufacturing

 *Corresponding authors
aChemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com
bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA
cPfizer, Sandwich, UK
dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland
eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
fSmall Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA
gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA
hChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA
iProcess Chemistry, Merck, Rahway, New Jersey 07065, USA
jProcess Development, Amgen, Thousand Oaks, USA
kMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa
lDelft University of Technology, 2628 BL Delft, Netherlands
Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim
Ingelheim am Rhein, Germany

Research experience

  • Feb 2002–Sep 2015
     Director
    Boehringer Ingelheim
    Germany · Nieder-Ingelheim
  • Aug 1996–Feb 1998
    Postdoc
    The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou
    United States · La Jolla
  • Aug 1992–Aug 1996
    PhD Candidate
    Rice University · Department of Chemistry
    United States · Houston
Supplementary References
1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.
2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.
3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.
4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.
5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.
6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.
7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.
8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.
9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.
10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.
11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.
12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.
13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.
14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.
15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.
16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.
17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

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Biocatalysis : Biological solutions to a growing world, Pregabalin case study

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Oct 022016
 

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Biocatalysis : Biological solutions to a growing world
– Mr. Michael Foldager, Global Marketing Manager – Biocatalysis, Novozymes A/S, Denmark

Michael Foldager

Michael Foldager

Global Marketing Manager
Novozymes, Copenhagen · Business Development

Copenhagen, Denmark

December 4th, 2015 at “IGCW 2015” in Mumbai. India
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Image result for NovozymesAmerikansk lovgivning holder hånden under Novozymes, når der tales om majsbaseret bioethanol, da det er lovfæstet, at 10 pct. af brændstofforbruget skal kommer fra biobrændstof

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Animal-free yeast production of Albumin offers huge therapeutic potential in medicine (Source: Albumedix)

 

///////////Biocatalysis, Biological solutions,  growing world, Pregabalin,  case study, Michael Foldager, Global Marketing Manager, Novozymes, Copenhagen

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Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries

 drugs  Comments Off on Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries
Jun 082016
 

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Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries

An Indian helping millions

9e3e7-new-india-map

MAKING INDIANS FEEL PROUD

LINK

https://newdrugapprovals.org/

////////blog, Dr Anthony , New Drug Approvals,  13 lakh views, 212 countries, India

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Printing with Collagen

 drugs  Comments Off on Printing with Collagen
May 132016
 

thumbnail image: Printing with Collagen

Printing with Collagen

Addition of collagen to hydrogels in 3D printing improves stem cell differentiation in osteogenesis

Read more

http://www.chemistryviews.org/details/news/9268521/Printing_with_Collagen.html

 

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Collagen

Tropocollagen molecule: three left-handed procollagens (red, green, blue) join to form a right handed triple helical tropocollagen.

Collagen is the most common protein found in mammals.

Collagen /ˈkɒlən/ is the main structural protein in the extracellular space in the various connective tissues in animal bodies. As the main component of connective tissue, it is the most abundant protein in mammals,[1] making up from 25% to 35% of the whole-body protein content. Depending upon the degree of mineralization, collagen tissues may be rigid (bone), compliant (tendon), or have a gradient from rigid to compliant (cartilage).[2] Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendons, ligaments and skin. It is also abundant incorneas, cartilage, bones, blood vessels, the gut, intervertebral discs and the dentin in teeth.[3] In muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles.[4] Thefibroblast is the most common cell that creates collagen.

Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed.[5] Collagen also has many medical uses in treating complications of the bones and skin.

The name collagen comes from the Greek κόλλα (kólla), meaning “glue“, and suffix -γέν, -gen, denoting “producing”.[6][7] This refers to the compound’s early use in the process of boiling the skin and sinews of horses and other animals to obtain glue.

 

 

woman receiving injection to forehead
Collagen injections can be used in cosmetic procedures to improve the contours of aging skin.

Types of collagen

Collagen occurs in many places throughout the body. Over 90% of the collagen in the human body, however, is type I.[8]

So far, 28 types of collagen have been identified and described. They can be divided into several groups according to the structure they form:[2]

  • Fibrillar (Type I, II, III, V, XI)
  • Non-fibrillar
    • FACIT (Fibril Associated Collagens with Interrupted Triple Helices) (Type IX, XII, XIV, XVI, XIX)
    • Short chain (Type VIII, X)
    • Basement membrane (Type IV)
    • Multiplexin (Multiple Triple Helix domains with Interruptions) (Type XV, XVIII)
    • MACIT (Membrane Associated Collagens with Interrupted Triple Helices) (Type XIII, XVII)
    • Other (Type VI, VII)

The five most common types are:

  • Type I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)
  • Type II: cartilage (main collagenous component of cartilage)
  • Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
  • Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
  • Type V: cell surfaces, hair and placenta

wrinkled mouth with cigarette
Tobacco contains chemicals that damage collagen

Medical uses

Cardiac applications

The collagenous cardiac skeleton which includes the four heart valve rings, is histologically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating septa of the heart chambers – the interventricular septum and the atrioventricular septum. Collagen contribution to the measure of cardiac performance summarily represents a continuous torsional force opposed to the fluid mechanics of blood pressure emitted from the heart. The collagenous structure that divides the upper chambers of the heart from the lower chambers is an impermeable membrane that excludes both blood and electrical impulses through typical physiological means. With support from collagen, atrial fibrillation should never deteriorate to ventricular fibrillation. Collagen is layered in variable densities with cardiac muscle mass. The mass, distribution, age and density of collagen all contribute to the compliance required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable pressure. Gradual calcium deposition within collagen occurs as a natural function of aging. Calcified points within collagen matrices show contrast in a moving display of blood and muscle, enabling methods of cardiac imaging technology to arrive at ratios essentially stating blood in (cardiac input) and blood out (cardiac output). Pathology of the collagen underpinning of the heart is understood within the category of connective tissue disease.

Hydrolyzed type II collagen and osteoarthritis

A published study[9] reports that ingestion of a novel low molecular weight hydrolyzed chicken sternal cartilage extract, containing a matrix of hydrolyzed type II collagen,chondroitin sulfate, and hyaluronic acid, relieves joint discomfort associated with osteoarthritis. A randomized controlled trial (RCT) enrolling 80 subjects demonstrated that it was well tolerated with no serious adverse event and led to a significant improvement in joint mobility compared to the placebo group on days 35 (p = 0.007) and 70 (p < 0.001).

 

Fast facts on collagen

Here are some key points about collagen. More detail and supporting information is in the main article.25-27

  • Protein makes up around 20% of the body’s mass, and collagen makes up around 30% of the protein in the human body.
  • There are at least 16 types of collagen, but 80-90% of the collagen in the body consists of types I, II, and III.
  • Type I collagen fibrils are stronger than steel (gram for gram).
  • Collagen is most commonly found within the body in the skin, bones and connective tissues.
  • The word “collagen” is derived from the Greek “kolla,” meaning glue.
  • Collagen gives the skin its strength and structure, and also plays a role in the replacement of dead skin cells.
  • Collagen production declines with age (as part of intrinsic aging), and is reduced by exposure to ultraviolet light and other environmental factors (extrinsic aging).
  • Collagen in medical products can be derived from human, bovine, porcine and ovine sources.
  • Collagen dressings attract new skin cells to wound sites.
  • Cosmetic products such as revitalizing lotions that claim to increase collagen levels are unlikely to do so, as collagen molecules are too large to be absorbed through the skin.
  • Collagen production can be stimulated through the use of laser therapy and the use of all-trans retinoic acid (a form ofvitamin A).
  • Controllable factors that damage the production of collagen include sunlight, smoking and high sugar consumption.

Cosmetic surgery

Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic, and surgical purposes. Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging.[10] Some points of interest are:

  1. When used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use.
  2. Most medical collagen is derived from young beef cattle (bovine) from certified BSE-free animals. Most manufacturers use donor animals from either “closed herds”, or from countries which have never had a reported case of BSE such as Australia, Brazil, and New Zealand.

Bone grafts

As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen is used in bone grafting as it has a triple helical structure, making it a very strong molecule. It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. The triple helical structure of collagen prevents it from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix.[11]

Tissue regeneration

Collagen scaffolds are used in tissue regeneration, whether in sponges, thin sheets, or gels. Collagen has the correct properties for tissue regeneration such as pore structure, permeability, hydrophilicity and it is stable in vivo. Collagen scaffolds are also ideal for the deposition of cells, such as osteoblasts and fibroblasts and once inserted, growth is able to continue as normal in the tissue.[12]

Reconstructive surgical uses

Collagens are widely employed in the construction of the artificial skin substitutes used in the management of severe burns. These collagens may be derived from bovine, equine, porcine, or even human sources; and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.

Collagen is also sold commercially in pill form as a supplement to aid joint mobility. However, because proteins are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect connective tissue in the body, except through the effect of individual amino acid supplementation.

Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular interactions with the extracellular environment.[13]

Wound care

Collagen is one of the body’s key natural resources and a component of skin tissue that can benefit all stages of the wound healing process.[14] When collagen is made available to the wound bed, closure can occur. Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided.

Collagen is a natural product, therefore it is used as a natural wound dressing and has properties that artificial wound dressings do not have. It is resistant against bacteria, which is of vital importance in a wound dressing. It helps to keep the wound sterile, because of its natural ability to fight infection. When collagen is used as a burn dressing, healthygranulation tissue is able to form very quickly over the burn, helping it to heal rapidly.[15]

Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing:

  • Guiding function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix.
  • Chemotactic properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing.
  • Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new collagen deposition and capillary growth.
  • Hemostatic properties: Blood platelets interact with the collagen to make a hemostatic plug.

Chemistry

The collagen protein is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2).[16] The amino acid composition of collagen is atypical for proteins, particularly with respect to its high hydroxyproline content. The most common motifs in the amino acid sequence of collagen are glycineproline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. The average amino acid composition for fish and mammal skin is given.[16]

Amino acid Abundance in mammal skin
(residues/1000)
Abundance in fish skin
(residues/1000)
Glycine 329 339
Proline 126 108
Alanine 109 114
Hydroxyproline 95 67
Glutamic acid 74 76
Arginine 49 52
Aspartic acid 47 47
Serine 36 46
Lysine 29 26
Leucine 24 23
Valine 22 21
Threonine 19 26
Phenylalanine 13 14
Isoleucine 11 11
Hydroxylysine 6 8
Methionine 6 13
Histidine 5 7
Tyrosine 3 3
Cysteine 1 1
Tryptophan 0 0

Synthesis

First, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. This step is important for later glycosylation and the formation of the triple helix structure of collagen. The hydroxylase enzymes that perform these reactions require Vitamin C as a cofactor, and a deficiency in this vitamin results in impaired collagen synthesis and the resulting disease scurvy[17] These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase[18] and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions. In this service, one molecule of vitamin C is destroyed for each H replaced by OH. [19] The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems, is the other form of collagen. All types of collagens are triple helices, and the differences lie in the make-up of the alpha peptides created in step 2.

  1. Transcription of mRNA: About 34 genes are associated with collagen formation, each coding for a specific mRNA sequence, and typically have the “COL” prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).
  2. Pre-pro-peptide formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm, it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal recognition particle on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. It is now known as pre-pro-collagen.
  3. Pre-pro-peptide to pro-collagen: Three modifications of the pre-pro-peptide occur leading to the formation of the alpha peptide:
    1. The signal peptide on the N-terminal is dissolved, and the molecule is now known as propeptide (not procollagen).
    2. Hydroxylation of lysines and prolines on propeptide by the enzymes ‘prolyl hydroxylase’ and ‘lysyl hydroxylase’ (to produce hydroxyproline and hydroxylysine) occurs to aid cross-linking of the alpha peptides. This enzymatic step requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).
    3. Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
    4. Once these modifications have taken place, three of the hydroxylated and glycosylated propeptides twist into a triple helix forming procollagen. Procollagen still has unwound ends, which will be later trimmed. At this point, the procollagen is packaged into a transfer vesicle destined for the Golgi apparatus.
  4. Golgi apparatus modification: In the Golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step, oligosaccharides (not monosaccharides as in step 3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.
  5. Formation of tropocollagen: Once outside the cell, membrane bound enzymes known as ‘collagen peptidases’, remove the “loose ends” of the procollagen molecule. What is left is known as tropocollagen. Defects in this step produce one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is absent when synthesizing type III, a type of fibrilar collagen.
  6. Formation of the collagen fibril: ‘Lysyl oxidase’, an extracellular enzyme, produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.

Action of lysyl oxidase

Amino acids

Collagen has an unusual amino acid composition and sequence:

  • Glycine is found at almost every third residue.
  • Proline makes up about 17% of collagen.
  • Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as acofactor.

Cortisol stimulates degradation of (skin) collagen into amino acids.[20]

Collagen I formation

Most collagen forms in a similar manner, but the following process is typical for type I:

  1. Inside the cell
    1. Two types of alpha chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.
    2. Polypeptide chains are released into the lumen of the RER.
    3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
    4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (vitamin C) as a cofactor.
    5. Glycosylation of specific hydroxylysine residues occurs.
    6. Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
    7. Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted by exocytosis.
  2. Outside the cell
    1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
    2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
    3. Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.

Synthetic pathogenesis

Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the 18th century, this condition was notorious among long-duration military, particularly naval, expeditions during which participants were deprived of foods containing vitamin C.

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis[21] may attack healthy collagen fibers.

Many bacteria and viruses secrete virulence factors, such as the enzyme collagenase, which destroys collagen or interferes with its production.

Molecular structure

A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. It is approximately 300 nm long and 1.5 nm in diameter, and it is made up of three polypeptide strands (called alpha peptides, see step 2), each of which has the conformation of a left-handed helix – this should not be confused with the right-handedalpha helix. These three left-handed helices are twisted together into a right-handed triple helix or “super helix”, a cooperative quaternary structure stabilized by many hydrogen bonds. With type I collagen and possibly all fibrillar collagens, if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.

Three polypeptides coil to form tropocollagen. Many tropocollagens then bind together to form a fibril, and many of these then form a fibre.

A distinctive feature of collagen is the regular arrangement ofamino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern GlyPro-X or Gly-X-Hyp, where X may be any of various other amino acid residues.[16] Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links.[16]This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin.

Collagen is not only a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its non-proline-rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.

Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish, whose body temperatures are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals.[16] The lower proline and hydroxproline contents of cold-water fish and other poikilotherm animals leads to their collagen having a lower thermal stability than mammalian collagen.[16] This lower thermal stability means that gelatin derived from fish collagen is not suitable for many food and industrial applications.

The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues.[22][23] Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors.[2] In the fibrillar collagens, the molecules are staggered from each other by about 67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing only four molecules, called the “gap”.[24] The triple-helices are also arranged in a hexagonal or quasihexagonal array in cross-section, in both the gap and overlap regions.[24][25]

There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils).[26] Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players.[23] Collagen’s insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell–cell and cell–matrix communication, and how tissues are constructed in growth and repair, and changed in development and disease.[27][28] For example, using AFM–based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.[29]

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) Ca10(OH)2(PO4)6.[30] Type I collagen gives bone its tensile strength.

Associated disorders

Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.

Genetic Defects of Collagen Genes
Type Notes Gene(s) Disorders
I This is the most abundant collagen of the human body. It is present in scar tissue, the end product when tissue heals by repair. It is found in tendons, skin, artery walls, cornea, the endomysiumsurrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth. COL1A1, COL1A2 Osteogenesis imperfecta, Ehlers–Danlos syndrome, Infantile cortical hyperostosis a.k.a. Caffey’s disease
II Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. COL2A1 Collagenopathy, types II and XI
III This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber. Also found in artery walls, skin, intestines and the uterus COL3A1 Ehlers–Danlos syndrome, Dupuytren’s contracture
IV Basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli ofnephron in the kidney. COL4A1, COL4A2,COL4A3, COL4A4,COL4A5, COL4A6 Alport syndrome, Goodpasture’s syndrome
V Most interstitial tissue, assoc. with type I, associated with placenta COL5A1, COL5A2,COL5A3 Ehlers–Danlos syndrome (Classical)
VI Most interstitial tissue, assoc. with type I COL6A1, COL6A2,COL6A3, COL6A5 Ulrich myopathy, Bethlem myopathy,Atopic dermatitis[31]
VII Forms anchoring fibrils in dermoepidermal junctions COL7A1 Epidermolysis bullosa dystrophica
VIII Some endothelial cells COL8A1, COL8A2 Posterior polymorphous corneal dystrophy 2
IX FACIT collagen, cartilage, assoc. with type II and XI fibrils COL9A1, COL9A2,COL9A3 EDM2 and EDM3
X Hypertrophic and mineralizing cartilage COL10A1 Schmid metaphyseal dysplasia
XI Cartilage COL11A1, COL11A2 Collagenopathy, types II and XI
XII FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans COL12A1
XIII Transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basement membranes like nidogen and perlecan. COL13A1
XIV FACIT collagen, also known as undulin COL14A1
XV COL15A1
XVI COL16A1
XVII Transmembrane collagen, also known as BP180, a 180 kDa protein COL17A1 Bullous pemphigoid and certain forms of junctional epidermolysis bullosa
XVIII Source of endostatin COL18A1
XIX FACIT collagen COL19A1
XX COL20A1
XXI FACIT collagen COL21A1
XXII COL22A1
XXIII MACIT collagen COL23A1
XXIV COL24A1
XXV COL25A1
XXVI EMID2
XXVII COL27A1
XXVIII COL28A1

In addition to the above-mentioned disorders, excessive deposition of collagen occurs in scleroderma.

Diseases

One thousand mutations have been identified in twelve out of more than twenty types of collagen. These mutations can lead to various diseases at the tissue level.[32]

Osteogenesis imperfecta – Caused by a mutation in type 1 collagen, dominant autosomal disorder, results in weak bones and irregular connective tissue, some cases can be mild while others can be lethal, mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen.[33]

Chondrodysplasias – Skeletal disorder believed to be caused by a mutation in type 2 collagen, further research is being conducted to confirm this.[34]

Ehlers-Danlos Syndrome – Six different types of this disorder, which lead to deformities in connective tissue. Some types can be lethal, leading to the rupture of arteries. Each syndrome is caused by a different mutation, for example type four of this disorder is caused by a mutation in collagen type 3.[35]

Alport syndrome – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, sufferers have problems with their kidneys and eyes, loss of hearing can also develop in during the childhood or adolescent years.[36]

Osteoporosis – Not inherited genetically, brought on with age, associated with reduced levels of collagen in the skin and bones, growth hormone injections are being researched as a possible treatment to counteract any loss of collagen.[37]

Knobloch syndrome – Caused by a mutation in the COL18A1 gene that codes for the production of collagen XVIII. Patients present with protrusion of the brain tissue and degeneration of the retina, an individual who has family members suffering from the disorder are at an increased risk of developing it themselves as there is a hereditary link.[32]

Characteristics

Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins, such as enzymes. Tough bundles of collagen calledcollagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and skin.[38][39] Along with elastin and soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging.[10] It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It may be one of the most abundant proteins in the fossil record, given that it appears to fossilize frequently, even in bones from the Mesozoic and Paleozoic.[40]

Uses

Collagen has a wide variety of applications, from food to medical. For instance, it is used in cosmetic surgery and burn surgery. It is widely used in the form of collagen casings for sausages, which are also used in the manufacture of musical strings.

If collagen is subject to sufficient denaturation, e.g. by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. random coils. This process describes the formation of gelatin, which is used in many foods, including flavoredgelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.[41] From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the essential amino acids in the proportions that the human body requires—they are not ‘complete proteins‘ (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary supplements usually containing hydrolyzed collagen claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims.[42]Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin, arthritis etc.) rather than just a protein deficiency.

From the Greek for glue, kolla, the word collagen means “glue producer” and refers to the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon-dated as more than 8,000 years old, was found to be collagen—used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.[43] Collagen normally converts to gelatin, but survived due to dry conditions. Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs—an application incompatible with tough, syntheticplastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.

Gelatin-resorcinolformaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs.[44]

History

The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s.[45][46] Since that time, many prominent scholars, including Nobel laureates Crick, Pauling, Rich and Yonath, and others, including Brodsky,Berman, and Ramachandran, concentrated on the conformation of the collagen monomer. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical “Madras” model of Ramachandran, which provided an essentially correct model of the molecule’s quaternary structure[47][48][49] although this model still required some refinement.[50] [clarification needed] [51][52][53][54] The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal or quasi-hexagonal.[25][55][56] As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is ‘sheet-like’ or microfibrillar.[50][57][58] The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy.[59][60][61] The microfibrillar structure of tail tendon, as described by Fraser, Miller, and Wess (amongst others), was modeled as being closest to the observed structure,[50] although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril.[24][62] Various cross linking agents like L-Dopaquinone, embeline, potassium embelate and 5-O-methyl embelin could be developed as potential cross-linking/stabilization agents of collagen preparation and its application as wound dressing sheet in clinical applications is enhanced.[63]

See also

References

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  55. Jump up^ Jesior, J. C.; Miller, A. & Berthet-Colominas, C. (1980). “Crystalline three-dimensional packing is general characteristic of type I collagen fibrils”. FEBS Lett 113 (2): 238–240.doi:10.1016/0014-5793(80)80600-4. PMID 7389896.
  56. Jump up^ Fraser, R. D. B. & MacRae, T. P. (1981). “Unit cell and molecular connectivity in tendon collagen”. Int. J. Biol. Macromol. 3 (3): 193–200. doi:10.1016/0141-8130(81)90063-5.
  57. Jump up^ Fraser, R. D.; MacRae, T. P.; Miller, A. (1987). “Molecular packing in type I collagen fibrils”. J Mol Biol 193 (1): 115–125. doi:10.1016/0022-2836(87)90631-0.PMID 3586015.
  58. Jump up^ Wess, T. J.; Hammersley, AP; et al. (1998). “Molecular packing of type I collagen in tendon”. J Mol Biol 275 (2): 255–267. doi:10.1006/jmbi.1997.1449. PMID 9466908.
  59. Jump up^ Raspanti, M.; Ottani, V.; Ruggeri, A. (1990). “Subfibrillar architecture and functional properties of collagen: a comparative study in rat tendons”. J Anat. 172: 157–164.PMC 1257211. PMID 2272900.
  60. Jump up^ Holmes, D. F.; Gilpin, C. J.; Baldock, C.; Ziese, U.; Koster, A. J.; Kadler, K. E. (2001).“Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization”. PNAS 98 (13): 7307–7312.Bibcode:2001PNAS…98.7307H. doi:10.1073/pnas.111150598. PMC 34664.PMID 11390960.
  61. Jump up^ Holmes, D. F.; Kadler, KE (2006). “The 10+4 microfibril structure of thin cartilage fibrils”. PNAS 103 (46): 17249–17254. Bibcode:2006PNAS..10317249H.doi:10.1073/pnas.0608417103. PMC 1859918. PMID 17088555.
  62. Jump up^ Okuyama, K; Bächinger, HP; Mizuno, K; Boudko, SP; Engel, J; Berisio, R; Vitagliano, L (2009). “Comment on Microfibrillar structure of type I collagen in situ by Orgel et al. (2006), Proc. Natl Acad. Sci. USA, 103, 9001–9005”. Acta Crystallogr D Biol Crystallogr 65 (Pt9): 1009–10. doi:10.1107/S0907444909023051. PMID 19690380.
  63. Jump up^ Narayanaswamy, Radhakrishnan; Shanmugasamy, Sangeetha; Shanmugasamy, Sangeetha; Gopal, Ramesh; Mandal, Asit (2011). “Bioinformatics in crosslinking chemistry of collagen with selective crosslinkers”. BMC Research Notes 4: 399. doi:10.1186/1756-0500-4-399.

External links

12 types of collagen

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Illegal Drugs in Dietary Supplements

 drugs  Comments Off on Illegal Drugs in Dietary Supplements
May 132016
 

thumbnail image: Illegal Drugs in Dietary Supplements

Illegal Drugs in Dietary Supplements

Forbidden stimulant oxilofrine found in various dietary supplements sold in the USA

Read more

http://www.chemistryviews.org/details/news/9278771/Illegal_Drugs_in_Dietary_Supplements.html

 

 

Oxilofrine (also known as methylsynephrine, hydroxyephrine, oxyephrine, and 4-HMP) is a stimulant drug[1] and is anamphetamine chemically related to ephedrine and to synephrine.

Oxilofrine is currently a WADA prohibited substance when used in competition.[2] It is an ingredient found in some dietary supplements.

Publicized cases

  • In 2009, Brazilian/American cyclist Flávia Oliveira was suspended for 2 years after taking a supplement known as “HyperDrive 3.0+” which contained methylsynephrine, a chemical equivalent of Oxilofrine, among other substances. [3] Her sentence was eventually reduced to 18 months after an appeal as there was enough evidence that she had unknowingly consumed said substance as the old label did not list methylsynephrine.[4]
  • On July 14, 2013, Jamaican runners Asafa Powell and Sherone Simpson tested positive for Oxilofrine prior to the 2013 World Athletics Championships. [5] Powell, however, maintained that he did not take any banned supplements knowingly or willfully.[6]Powell voluntarily withdrew as a result of the test. On 10 April 2014, both athletes received an 18-month suspension from competing, which was set to expire in December that year.[7] However, after appealing to the Court of Arbitration for Sport (CAS), both athletes’ suspensions were lifted on 14 July 2014.[8]
  • On July 16, 2015, Boston Red Sox pitching prospect Michael Kopech was suspended without pay for 50 games after testing positive for Oxilofrine, which is a banned substance under the Minor League Drug Prevention and Treatment Program. Kopech denied knowingly taking the substance.[9]

 

 

 

 

References

  1.  Fourcroy, Jean L. (2008). Pharmacology, doping and sports: a scientific guide for athletes, coaches, physicians, scientists and administrators. Taylor & Francis. ISBN 978-0-415-42845-3.
  2.  http://list.wada-ama.org/prohibited-in-competition/prohibited-substances/
  3.  Charles Pelkey (2010-04-13). “Oliveira suspended for two years”. Velonews.
  4.  Charles Pelkey (2011-02-24). “Court of Arbitration for Sport reduces Flavia Oliveira suspension”. Velonews.
  5.  Reuters. “Jamaicans Powell, Simpson test positive – SuperSport – Athletics”. SuperSport. Retrieved 2013-07-15.
  6.  “Jamaican Sprinter Asafa Powell slapped 18-month ban for doping”. IANS. news.biharprabha.com. Retrieved 10 April 2014.
  7.  “Asafa Powell banned for 18 months for doping”. BBC Sport. 10 April 2014. Archived from the original on 9 May 2014.
  8.  Drayton, John (14 July 2014). “Asafa Powell and Sherone Simpson given green light to return to action after sprinters have doping bans reduced to six months”. Mail Online. Retrieved14 July 2014.
  9.  Danny Wild (16 July 2015). “Red Sox No. 10 prospect Kopech suspended”. MiLB.com. Retrieved 8 March 2016
Oxilofrine
Oxilofrin Structural Formulae V.1.svg
Systematic (IUPAC) name
(1S*,2R*)-(±)-4-(1-Hydroxy-2-methylamino-propyl)phenol
Legal status
Legal status
  • Uncontrolled
Identifiers
CAS Number 365-26-4 
ATC code none
PubChem CID 9701
ChemSpider 9320 Yes
UNII F49638UBDR Yes
KEGG D08314 Yes
ChEMBL CHEMBL30400 Yes
Chemical data
Formula C10H15NO2
Molar mass 181.23 g/mol

////Illegal Drugs, Dietary Supplements, Forbidden stimulant , oxilofrine, dietary supplements ,  USA, Oxilofrine

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Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride

 drugs  Comments Off on Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride
May 032016
 

 

image

 

 

Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride

Original Research Article

Pages 482-490

Ying Peng, Jie Li, Jing Li, Yin Fei, Jiangnan Dong, Weisan Pan

International Journal of Pharmaceutics

Volume 441, Issues 1–2, Pages 1-834 (30 January 2013)

  • Delivery of venlafaxine hydrochloride with thermosensitive chitosan hydrogels system: diffusion controlled release and kinetic gelation mechanism is nucleation and growth.
  • Abstract

    Chitosan/glycerophosphate disodium (GP) thermosensitive hydrogels were prepared for the sustained delivery of venlafaxine hydrochloride (VH) and optimization of this formulation was mainly studied. Release mechanism was investigated by applying various mathematical models to the in vitro release profiles. Overall, drug release from the hydrogels showed best fit in first-order model and drug release mechanism was diffusion-controlled release. Optimization of VH chitosan/GP thermosensitive hydrogels was conducted by using a three-level three-factorial Box–Behnken experimental design to evaluate the effects of considered variables, the strength of the formulation, chitosan concentration and GP amount, on the selected responses: cumulative percentage drug release in 1 h, 24 h and the rate constant. It presented that higher strength and GP concentration resulted in higher initial release and rate constant, which supported the hypothesis that the kinetic gelation mechanism of this system was nucleation and growth. Drug release profiles illustrated that controlled drug delivery could be obtained over 24 h, which confirmed the validity of optimization. In vivo pharmacokinetic study was investigated and it demonstrated that compared with VH solution, chitosan/GP thermosensitive hydrogels had a better sustained delivery of VH.

///////Optimization, thermosensitive chitosan hydrogels, sustained delivery, venlafaxine hydrochloride

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Twelve Principles for Drug Optimization

 DRUG DESIGN, drugs  Comments Off on Twelve Principles for Drug Optimization
Jan 092016
 

 

Twelve Principles for Drug Optimization
1. Increasing Potency
In the analogue class of the histamine H2-receptor antagonists (cimetidine, nizatidine, ranitidine, roxatidine, and famotidine), an increasing potency of the drug analogues can be observed. Famotidine is the most potent member of this class.
2. Improving the Ratio of the Main Activity to Adverse Affects
The pioneer drug of the adrenergic β-blockers is propranolol, which blocked both β1– and β2-receptors. However, blocking β2-receptors in asthma is harmful. Several selective blockers were developed and used in cardiology, such as atenolol, metoprolol, etc.

3. Improving the Physicochemical Properties with the Help of Analogues
Benzylpenicillin (penicillin G) was a pioneer antibiotic molecule, which could be administered only by intramuscular injection because of its acid-sensitivity. Through analogues, stable molecules were obtained and they could be given orally (e.g., ampicillin).

4. Decreasing Resistance to Anti-Infective Drugs
Resistance to anti-infective drugs has become an increasing problem all over the world. The widespread use of penicillin G led to an alarming increase of penicillin-G resistant Staphylococcus aureus infections in 1960. A solution to the problem was the design of penicillinase-resistant penicillins. Several examples show that analogues can also overcome the resistance to antifungal and antiviral drugs.

5 .Decreasing Resistance to Anticancer Agents
Imatinib is the pioneer drug for the treatment of chronic myelogenous leukemia. However, a significant number of patients develop resistance to imatinib. New analogues, such as dasatinib and nilotinib, have been introduced recently and it is hoped that these analogues will be effective in imatinib-resistant cases.

6. Improving Oral Bioavailability
A good oral bioavailability is necessary in most cases because the oral application of a drug is preferred to an injection therapy. Enalaprilat is an angiotensin-converting enzyme inhibitor which is used in intravenous administration for the treatment of hypertensive emergencies. Its ester prodrug has an excellent oral bioavailability, but it requires hydrolysis by esterases. Analogue-

based drug research afforded the lysylproline analogue, lisinopril, which has an acceptable bioavailability and it does not require metabolic activation.

7. Long-Acting Drugs for Chronic Diseases
Quaternary antimuscarinics are important drugs for the treatment of chronic obstructive pulmonary disease. Ipratropium bromide is a very active bronchodilator that is used several times daily. Its analogue is tiotropium with a longer duration of action which enables a once-daily dosing.

8. Ultrashort-Acting Drugs in Emergency Cases
Esmolol is an adrenergic β1-selective blocker with a very short duration of action. It is used when β-blockade of very short duration is desired in emergency situations.

9. Decreasing Interindividual Pharmacokinetic Differences
Omeprazole is a pioneer proton pump inhibitor that shows interindividual variability. Analogue-based drug discovery afforded pantoprazole with a linear, highly predictable pharmacokinetic property.

10. Decreasing Systemic Activities
For intranasal and inhalation applications of corticosteroids in the treatment of asthma and rhinitis, it is important to decrease the systemic availability of these drugs to avoid their adverse effects. Analogue research afforded budenoside and fluticasone with a low oral bioavailability.

11. Decreasing Drug Interactions with the Help of Analogues
Cimetidine inhibits CYPs, an important class of drug-metabolizing enzymes. This interaction inhibits the metabolism of certain drugs, such as propranolol, warfarin, diazepam, thus producing effects equivalent to an overdose of these medicines. These effects are avoided by analogues such as ranitidine and famotidine.

12. Synergistic Interactions between Analogues
Analogue-based drug research starting from ritonavir, which is an HIV-1 protease inhibitor, afforded the more potent lopinavir. However, it has a low plasma half- life. A combination of ritonavir and lopinavir is very successful, because ritonavir inhibits the P-450-mediated metabiolism of lopinavir.

 

Standalone Drugs Can Be Starting
Points for Drug Optimizations

We analyzed the Top 100 most frequently used drugs and nine standalone drugs were identified, that is, pioneer drugs for which there are no effective analogues. These are the following drugs: acetaminophen, acetylsalicylic acid, aripiprazole, bupropion, ezetimibe, lamotrigine, metformin, topiramate, and valproate semisodium.

Acetaminophen is one of the oldest drugs, which even nowadays has a broad application as an analgesic and antipyretic agent. However, acute overdose can cause severe hepatic damage.

Acetylsalicylic acid (aspirin) is also one of the oldest drugs and, contrary to acetaminophen, its mechanism of action is partly known: it irreversibly inhibits the cyclooxygenase-1 enzyme. A more potent derivative with a better adverse effect profile would be advantageous.

Aripiprazole is a relatively new antipsychotic drug which acts as a dopamine partial agonist for the treatment of schizophrenia. A more effective drug is needed for the treatment of refractory patients, to improve treatment of negative symptoms and cognitive dysfunction.

Bupropion is a unique antidepressant drug. It is the first non-nicotine medication for the treatment of smoking cessation.
Ezetimibe is a relatively new cholesterol absorption inhibitor. Its mechanism of action was discovered only recently (2005). Analogue-based drug research is underway.

Lamotrigine, topiramate, and valproate are widely used anticonvulsant drugs, whose mechanism of action is not known. Several efforts have been made to find better analogues, so far without positive results.

Metformin is already an old standalone drug for the treatment of type 2 diabetes. It is used alone or in combination with new antidiabetic agents. Its mechanism of action is not known which makes it difficult to conduct an analogue-based drug research.

 

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