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[[File:Colesterol.png|thumb|right|350px|[[Cholesterol]]. A [[prototype|prototypical]] animal sterol and precursor, via [[steroidogenesis]], to most other animal steroids shown with its approved ring and atom conventions.<ref name="IUPAC"/>]]
[[File:Colesterol.png|thumb|right|350px|[[Cholesterol]]. A [[prototype|prototypical]] animal sterol and precursor, via [[steroidogenesis]], to most other animal steroids shown with its approved ring and atom conventions.<ref name="IUPAC"/>]]
[[File:Cholsäure.svg|thumb|200px|A [[bile acid]]. The more complex structure of the steroid [[cholic acid]].]]
[[File:Cholsäure.svg|thumb|200px|A [[bile acid]]. The more complex structure of the steroid [[cholic acid]].]]
A '''steroid''' is a type of [[organic compound]] that contains a characteristic arrangement of four [[cycloalkane]] rings that are joined to each other. Examples of steroids include the dietary [[lipid]] [[cholesterol]], bile acids, the sex hormones [[estradiol]] and [[testosterone]], and the [[anti-inflammatory]] drug [[dexamethasone]].<ref name = "Lednicer_2011">{{Cite book | author = Lednicer D | title = Steroid Chemistry at a Glance | year = 2011 | publisher = Wiley | location = Hoboken | isbn = 978-0-470-66084-3 }}</ref>{{page needed}}
A '''steroid''' is a type of [[organic compound]] that contains a characteristic arrangement of four [[cycloalkane]] rings that are joined to each other. Examples of steroids include the dietary [[lipid]] [[cholesterol]], bile acids, the sex hormones [[estradiol]] and [[testosterone]],<ref name = "Lednicer_2011">{{Cite book | author = Lednicer D | title = Steroid Chemistry at a Glance | year = 2011 | publisher = Wiley | location = Hoboken | isbn = 978-0-470-66084-3 }}</ref>{rp|10–19}} and the [[anti-inflammatory]] drug [[dexamethasone]].<ref name="pmid16236742">{{cite journal | author = Rhen T, Cidlowski JA | title = Antiinflammatory action of glucocorticoids — new mechanisms for old drugs | journal = N. Engl. J. Med. | volume = 353 | issue = 16 | pages = 1711–23 | year = 2005 | pmid = 16236742 | doi = 10.1056/NEJMra050541 | url = https://pedclerk.uchicago.edu/sites/pedclerk.uchicago.edu/files/uploads/Addison'sGCTx.NEJM_.2005.pdf }}</ref>


The core of steroids is composed of seventeen [[carbon]] atoms bonded together that take the form of four fused rings: three [[cyclohexane]] rings (designated as rings A, B and C in the figure to the right) and one [[cyclopentane]] ring (the D ring). The steroids vary by the functional groups attached to this four-ring core and by the [[oxidation state]] of the rings. [[Sterol]]s are special forms of steroids, with a [[hydroxyl]] group at position-3 and a skeleton derived from [[cholestane]].<ref name="IUPAC">{{cite journal | journal = [[Pure and Applied Chemistry|Pure & Appl. Chem.]] | volume = 61 | issue = 10 | pages = 1783–1822 | year = 1989 | title = Nomenclature of Steroids (Recommendations 1989) | author = Moss GP | doi = 10.1351/pac198961101783 | url = http://www.chem.qmul.ac.uk/iupac/steroid/ }} [http://iupac.org/publications/pac/pdf/1989/pdf/6110x1783.pdf PDF] {{cite journal | author = | title = IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 | journal = Eur. J. Biochem. | volume = 186 | issue = 3 | pages = 429–58 |date=December 1989 | pmid = 2606099 | doi = 10.1111/j.1432-1033.1989.tb15228.x | url = }}</ref>
The core of steroids is composed of seventeen [[carbon]] atoms bonded together that take the form of four fused rings: three [[cyclohexane]] rings (designated as rings A, B and C in the figure to the right) and one [[cyclopentane]] ring (the D ring). The steroids vary by the functional groups attached to this four-ring core and by the [[oxidation state]] of the rings. [[Sterol]]s are special forms of steroids, with a [[hydroxyl]] group at position-3 and a skeleton derived from [[cholestane]].<ref name="IUPAC">{{cite journal | journal = [[Pure and Applied Chemistry|Pure & Appl. Chem.]] | volume = 61 | issue = 10 | pages = 1783–1822 | year = 1989 | title = Nomenclature of Steroids (Recommendations 1989) | author = Moss GP | doi = 10.1351/pac198961101783 | url = http://www.chem.qmul.ac.uk/iupac/steroid/ }} [http://iupac.org/publications/pac/pdf/1989/pdf/6110x1783.pdf PDF] {{cite journal | author = | title = IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 | journal = Eur. J. Biochem. | volume = 186 | issue = 3 | pages = 429–58 | date= December 1989 | pmid = 2606099 | doi = 10.1111/j.1432-1033.1989.tb15228.x }}</ref>


Hundreds of distinct steroids are found in [[plant]]s, [[animal]]s and [[Fungus|fungi]]. All steroids are made in cells either from the sterols [[lanosterol]] (animals and fungi, see below right) or from [[cycloartenol]] (plants). Both lanosterol and cycloartenol are derived from the cyclization of the [[triterpene]] [[squalene]].<ref name="urlLanosterol biosynthesis">{{cite web | url = http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/terp/lanost.html | title = Lanosterol biosynthesis | publisher = International Union Of Biochemistry And Molecular Biology | work = Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology }}</ref>
Hundreds of distinct steroids are found in [[plant]]s, [[animal]]s and [[Fungus|fungi]]. All steroids are made in cells either from the sterols [[lanosterol]] (animals and fungi, see below right) or from [[cycloartenol]] (plants). Both lanosterol and cycloartenol are derived from the cyclization of the [[triterpene]] [[squalene]].<ref name="urlLanosterol biosynthesis">{{cite web | url = http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/terp/lanost.html | title = Lanosterol biosynthesis | publisher = International Union Of Biochemistry And Molecular Biology | work = Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology }}</ref>

Revision as of 06:08, 12 May 2014

This article is about a family of polycyclic hydrocarbons. For the performance-enhancing substance, see Anabolic steroid.
Gonane. The simplest steroid and a substructure present in all other steroids, shown with its IUPAC-approved ring lettering and atom numbering.[1]
Cholesterol. A prototypical animal sterol and precursor, via steroidogenesis, to most other animal steroids shown with its approved ring and atom conventions.[1]
A bile acid. The more complex structure of the steroid cholic acid.

A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary lipid cholesterol, bile acids, the sex hormones estradiol and testosterone,[2]{rp|10–19}} and the anti-inflammatory drug dexamethasone.[3]

The core of steroids is composed of seventeen carbon atoms bonded together that take the form of four fused rings: three cyclohexane rings (designated as rings A, B and C in the figure to the right) and one cyclopentane ring (the D ring). The steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are special forms of steroids, with a hydroxyl group at position-3 and a skeleton derived from cholestane.[1]

Hundreds of distinct steroids are found in plants, animals and fungi. All steroids are made in cells either from the sterols lanosterol (animals and fungi, see below right) or from cycloartenol (plants). Both lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.[4]

Lanosterol, the biosynthetic precursor to animal steroids. The total number of carbons (30) reflects its triterpenoid origin.

Nomenclature

As IUPAC guidance notes (and is explained more fully following the quote),

"Steroids are compounds possessing the skeleton of cyclopenta[a]phenanthrene or a skeleton derived therefrom by one or more bond scissions or ring expansions or contractions. Methyl groups are normally present at C-10 and C-13. An alkyl side chain may also be present at C-17.Sterols are steroids carrying a hydroxyl group at C-3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain."[5]

Gonane, above, is the simplest possible steroid and is composed of seventeen carbon atoms in carbon-carbon bonds that form four fused rings in a defined three-dimensional shape. The three cyclohexane rings (designated as rings A, B, and C in the gonane and cholesterol figures above right) form the skeleton of a perhydro- derivative of phenanthrene. The D-ring has a cyclopentane structure; hence, though it is uncommon, per IUPAC steroids can also be named as various hydro-derivatives of cyclopenta[a]phenanthrene.[6] When the two methyl groups and 8-carbon side chain (at C17, as shown for cholesterol) are present, the steroid is said to have a cholestane framework.

In addition to the noted ring scissions (cleavages), and expansions and contractions (cleavage and reclosing to a larger or smaller rings)—all variations in the steroid carbon-carbon bond framework—steroids can also vary in the bond orders within the rings, in the number of methyl groups attached to the ring (and, when present, on the prominent side chain at C17), in the functional groups attached to the rings and side chain, and by the configuration of groups attached to the rings and chain.[2]: 2–9  For instance, sterols such as cholesterol and lanosterol, above, have an hydroxyl group attached at position C-3, while testosterone and progesterone, below, have a carbonyl (oxo substituent) at C3; of these examples, lanosterol alone has two methyl groups at C4, and cholesterol with a C4-C5 double bond differs from testosterone and progesterone, which have a C5-C6 double bond.

Types

Taxonomical/functional

Some of the common categories of steroids:

Structural: Intact ring system

It is also possible to classify steroids based upon their chemical composition. One example of how MeSH performs this classification is available at the Wikipedia MeSH catalog. Examples from this classification include:

Cholecalciferol (vitamin D3), an example of a 9,10-secosteroid. The triene substructure attached to the ring bearing the hydroxyl group is a result of the B-ring scission (cleavage) of the parent steroid framework, giving rise to this secosteroid. (The hydroxyl group is in position C3 of the parent steroid A-ring.)
Class Examples Number of carbon atoms
Cholestanes cholesterol 27
Cholanes cholic acid 24
Pregnanes progesterone 21
Androstanes testosterone 19
Estranes estradiol 18

The gonane (or steroid nucleus) is the parent (17-carbon tetracyclic) hydrocarbon molecule without any alkyl sidechains.[7]

Structural: Cleaved rings (secosteroids)

Secosteroids (L. seco, "to cut") are a subclass of steroidal compounds resulting, biosynthetically or conceptually, via scission (cleavage) of parent steroid rings, generally one of the four. Major secosteroid subclasses are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D3, is in the important 9,10-secosteroid subclass, derived via cleavage between carbon atoms C9 and C10 of the steroid B-ring (similarly 5,6-secosteroids, 13,14-steroids, etc.).[8]

Biological significance

Steroid and their metabolites are frequently used signalling molecules. The most notable examples are the steroid hormones.

Steroids along with phospholipids function as components of cell membranes. Steroids such as cholesterol decrease membrane fluidity.[9]

Similar to lipids, steroids represent highly concentrated energy stores. However, steroids are not typically used as sources of energy. In mammals, they are normally metabolized and excreted.

Pharmacological actions

A number of drugs target the mevalonate pathway:

Biosynthesis and metabolism

Simplified version of latter part of steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (PP or IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and, finally, lanosterol, the first steroid in the pathways. Some intermediates are omitted for clarity.

Steroid biosynthesis is an anabolic metabolic pathway that produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals compared to many other organisms, making the pathway a common target for antibiotics and other anti-infective drugs. In addition, steroid metabolism in humans is the target of cholesterol-lowering drugs such as statins.

In humans and other animals, the biosynthesis of steroids follows the mevalonate pathway that uses acetyl-CoA as building-blocks to form dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).[10] In subsequent steps, DMAPP and IPP are joined to form geranyl pyrophosphate (GPP), which in turn is used to synthesize the steroid lanosterol. Further modifications of lanosterol into other steroids are classified steroidogenesis transformations.

Mevalonate pathway

Main article: Mevalonate pathway
Mevalonate pathway

The mevalonate pathway or HMG-CoA reductase pathway starts with acetyl-CoA and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).

DMAPP and IPP in turn donate isoprene units, which are assembled and modified to form terpenes and isoprenoids,[11] which are a large class of lipids that include the carotenoids, and form the largest class of plant natural products.[12]

Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.[13] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.[13][14]

Steroidogenesis

The human steroidogenesis, with the major classes of steroid hormones, individual steroids and enzymatic pathways. Note that changes in molecular structure compared to the respective precursor are highlighted with white circles.

Steroidogenesis is the biological process by which steroids are generated from cholesterol and transformed into other steroids.[15] The pathways of steroidogenesis differ between different species – as an example the pathways of human steroidogenesis are shown in this figure below: Following is a list of the major classes of steroid hormones and some prominent members, with examples of major related functions:

Locations of human steroidogenesis:

  • Progestogens serve as precursors to all other human steroids – thus all human tissues which produce steroids must first convert cholesterol to pregnenolone. This conversion is the rate-limiting step of steroid synthesis, which occurs inside the mitochondrion of the respective tissue.[16]
  • Corticosteroids are produced in the adrenal cortex.
  • Estrogen and progesterone are made primarily in the ovary and in the placenta during pregnancy, and testosterone in the testes.
  • Testosterone is also converted into estrogen to regulate the supply of each, in the bodies of both females and males.
  • In addition, certain neurons and glia in the central nervous system (CNS) express the enzymes that are required for the local synthesis of pregnane neurosteroids, either de novo or from peripherally derived sources.

Regulation

Several key enzymes can be activated through DNA transcriptional regulation on activation of SREBP (Sterol Regulatory Element-Binding Protein-1 and -2).[citation needed] This intracellular sensor detects low cholesterol levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing lipoprotein uptake by up-regulating the LDL receptor.[citation needed] Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.[citation needed]

Alternative pathways

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[11][17]

Metabolism

Steroids are oxidized mainly by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring and allow the structure to be broken up by other enzymes, to form bile acids as final products.[18] These bile acids can then be eliminated through secretion from the liver in the bile.[19] The expression of this oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.[20]

Isolation, structure determination, and methods of analysis

The isolation of steroids refers, depending on context, either to the isolation of the considerable quantities of pure chemical matter required for chemical structure elucidation, derivitzation/degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but historically, often more),[21] or to the isolation of "analytical quantities" of the substance of interest, where the focus is on identification and quantitation of the substance (e.g., in biological tissue or fluid), and where the amount isolated depends on the analytical method applied (but is generally always sub-microgram in scale).[22][page needed] The methods of isolation applied toward achieving these two distinct scales of product are likewise distinct, but generally involve extraction, precipitation, adsorptions, chromatography, and sometimes crystallizations. In both cases, the isolated substance is purified to chemical homogeneity, i.e., specific combined separation and analytical methods such as LC-MS methods are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—with the goal being detection of only a single species present in the purportedly pure sample. The expression structure determination refers to methods that are applied to determine the chemical structure of an isolated, pure steroid, a process that involves an array of chemical and physical methods that have changed markedly over the history of steroid research, but that have included NMR and small molecule crystallography.[2]: 10–19  Methods of analysis include samplings of both of these prior areas, but especially analytical methods aimed at determining if a steroid is present in an analytical mixture, and determining its quantity in that medium.[22]

Chemical synthesis of steroids

Microbial transformations

Phytosterols, for instance, mixtures of soybean sterols, can be used as starting materials and converted into two kinds of steroid hormone intermediates through microbial transformation.[citation needed] Microbial catabolism of phytosterol sidechains yields either C-19 steroids, a precursor to most steroid hormones including sex hormones, or C-22 steroids, a precursor to adrenocortical hormones.[23][24]

Partial and total chemical synthesis

The chemical conversion of sapogenins to steroids—e.g., via the Marker degradation—is a method of partial synthesis that is a long-established alternative to microbial transformation of phytosterols to steroids, and underpinned Syntex efforts using the Mexican barbasco trade (harvesting and marketing large tubers of wild-growing plants, e.g., yams) to produce early synthetic steroids.[citation needed]

History

A number of Nobel Prizes have been awarded for research involving steroids. These prizes include:

See also

References

  1. ^ a b c Moss GP (1989). "Nomenclature of Steroids (Recommendations 1989)". Pure & Appl. Chem. 61 (10): 1783–1822. doi:10.1351/pac198961101783. PDF "IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989". Eur. J. Biochem. 186 (3): 429–58. December 1989. doi:10.1111/j.1432-1033.1989.tb15228.x. PMID 2606099.
  2. ^ a b c Lednicer D (2011). Steroid Chemistry at a Glance. Hoboken: Wiley. ISBN 978-0-470-66084-3.
  3. ^ Rhen T, Cidlowski JA (2005). "Antiinflammatory action of glucocorticoids — new mechanisms for old drugs" (PDF). N. Engl. J. Med. 353 (16): 1711–23. doi:10.1056/NEJMra050541. PMID 16236742.
  4. ^ "Lanosterol biosynthesis". Recommendations on Biochemical & Organic Nomenclature, Symbols & Terminology. International Union Of Biochemistry And Molecular Biology.
  5. ^ G.P. Moss and the Working Party of the IUPAC-IUB Joint Commission on Biochemical Nomenclature, "The Nomenclature of Steroids", hosted at Queen Mary University of London, Section 3S-1. See [1] and [2], accessed 10 May 2014. Also available from same authors at Pure Appl. Chem. 1989, 61, 1783-1822 or R.A. Hill, D.N. Kirk, H.L.J. Makin, H.L.J. & G.M. Murphy, 1991, "Dictionary of Steroids" London:Chapman and Hall, pp. xxx-lix. The Working Party of the IUPAC-IUB JCBN were P. Karlson (chairman), J.R. Bull, K. Engel, J. Fried†, H.W. Kircher, K.L. Loening, G.P. Moss, G. Popják and M.R. Uskokovic.
  6. ^ CID 130801 from PubChem; 219-08-9 cyclopentaphenanthrene
  7. ^ Edgren RA, Stanczyk FZ (December 1999). "Nomenclature of the gonane progestins". Contraception. 60 (6): 313. doi:10.1016/S0010-7824(99)00101-8. PMID 10715364.
  8. ^ Hanson JR (2010). "Steroids: partial synthesis in medicinal chemistry". Nat Prod Rep. 27 (6): 887–99. doi:10.1039/c001262a. PMID 20424788. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Sadava D, Hillis DM, Heller HC, Berenbaum MR (2011). Life: The Science of Biology 9th Edition. San Francisco: Freeman. pp. 105–114. ISBN 1-4292-4646-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  10. ^ Grochowski L, Xu H, White R (2006). "Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate". J Bacteriol. 188 (9): 3192–8. doi:10.1128/JB.188.9.3192-3198.2006. PMC 1447442. PMID 16621811.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Kuzuyama T, Seto H (2003). "Diversity of the biosynthesis of the isoprene units". Nat Prod Rep. 20 (2): 171–83. doi:10.1039/b109860h. PMID 12735695.
  12. ^ Dubey V, Bhalla R, Luthra R (2003). "An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants" (PDF). J Biosci. 28 (5): 637–46. doi:10.1007/BF02703339. PMID 14517367.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ a b Schroepfer G (1981). "Sterol biosynthesis". Annu Rev Biochem. 50: 585–621. doi:10.1146/annurev.bi.50.070181.003101. PMID 7023367.
  14. ^ Lees N, Skaggs B, Kirsch D, Bard M (1995). "Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review". Lipids. 30 (3): 221–6. doi:10.1007/BF02537824. PMID 7791529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis". J Steroid Biochem Mol Biol. 43 (8): 779–804. doi:10.1016/0960-0760(92)90307-5. PMID 22217824.
  16. ^ Rossier MF (2006). "T channels and steroid biosynthesis: in search of a link with mitochondria". Cell Calcium. 40 (2): 155–64. doi:10.1016/j.ceca.2006.04.020. PMID 16759697.
  17. ^ Lichtenthaler H (1999). "The 1-Dideoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants". Annu Rev Plant Physiol Plant Mol Biol. 50: 47–65. doi:10.1146/annurev.arplant.50.1.47. PMID 15012203.
  18. ^ Pikuleva IA (2006). "Cytochrome P450s and cholesterol homeostasis". Pharmacol. Ther. 112 (3): 761–73. doi:10.1016/j.pharmthera.2006.05.014. PMID 16872679.
  19. ^ Zollner G, Marschall HU, Wagner M, Trauner M (2006). "Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations". Mol. Pharm. 3 (3): 231–51. doi:10.1021/mp060010s. PMID 16749856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Kliewer S, Goodwin B, Willson T (2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocr. Rev. 23 (5): 687–702. doi:10.1210/er.2001-0038. PMID 12372848.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ American Chemical Society, International Historic Chemical Landmark, 1999, "Russell Marker and the Mexican Steroid Hormone Industry," see [3], accessed 10 May 2104.
  22. ^ a b Makin HLJ, Gower DB (2010). Steroid analysis. Dordrecht; New York: Springer. ISBN 978-1-4020-9774-4.
  23. ^ Conner AH, Nagaoka M, Rowe JW, Perlman D (August 1976). "Microbial conversion of tall oil sterols to C19 steroids" (PDF). Appl. Environ. Microbiol. 32 (2): 310–1. PMC 170056. PMID 987752.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Wang F-Q, Yao K, Wei D-Z. "From Soybean Phytosterols to Steroid Hormones, Soybean and Health". In El-Shemy H (ed.). Soybean and Health. InTech. doi:10.5772/18808. ISBN 978-953-307-535-8. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)CS1 maint: multiple names: authors list (link)
  25. ^ "The Nobel Prize in Chemistry 1927". The Nobel Foundation.
  26. ^ "The Nobel Prize in Chemistry 1928". The Nobel Foundation.
  27. ^ "The Nobel Prize in Chemistry 1939". The Nobel Foundation.
  28. ^ "The Nobel Prize in Physiology or Medicine 1950". The Nobel Foundation.
  29. ^ "The Nobel Prize in Chemistry 1965". The Nobel Foundation.
  30. ^ "The Nobel Prize in Chemistry 1969". The Nobel Foundation.
  31. ^ "The Nobel Prize in Chemistry 1975". The Nobel Foundation.

Further reading

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