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DOXYCYCLINE
and other Tetracyclines
CH3
OH
H
NMe2
H
OH
NH2
OH
OH
O
OH
O
O
doxycycline
Why is it important?
In the wake of the attacks on the Twin Towers in New York on 11th September 2001,
several letters containing anthrax spores were sent to two U. S. Senators and to
various media outlets. Five people died of inhalational anthrax and seventeen others
were taken ill. Bruce Edwards Ivins, a scientist at the U. S. government's bio-defence
laboratories at Fort Detrick, Maryland, came under suspicion, and he committed
suicide on July 27th 2008.
The anthrax outbreaks led to people suspected of exposure to anthrax being given the
drug Cipro (Ciprofloxacin) but Doxycycline was recommended as an equally
effective and cheaper alternative. Doxycycline (vibramycin) is effective against
several diseases, including Yersinia pestis (bubonic plague), Lyme disease and Rocky
Mountain spotted fever, as well as anthrax.
Is it a natural medicine?
Doxycycline is synthetic, but some tetracyclines are produced naturally by
Streptomyces bacteria, such as chlorotetracycline (Aureomycin), which was the first
one to be discovered; it was isolated from Streptomyces aurofaciens obtained from
samples of Missouri soil in 1945 and marketed as a medicine in 1948.
Cl
HO CH3
H
NMe2
H
OH
NH2
OH
OH
O
OH
O
O
chlorotetracycline
In 1952 it was found that you could hydrogenate chlorotetracycline under mild
conditions (H2; Pd/C catalyst) and produce tetracycline itself (link to October 2001
MOTM here). Pfizer isolated oxytetracycline from Streptomyces rimosus in the soil
near their Indiana plant. A research team led by the great R. B. Woodward of Harvard
went to work to solve the structure and published it in 1953.
Woodward picture at
http://en.wikipedia.org/wiki/File:Robert_Burns_Woodward_in_1965.jpg
or
http://www.ebeijing.gov.cn/feature_2/Noble_Forum_2008/Nobel_History/Nobel_Priz
e_Chemistry/W020081107564028609621.jpg
HO CH3
H
NMe2
OH
H
OH
NH2
OH
OH
OH
O
O
O
oxytetracycline
Another Nobel laureate, D. H. R. Barton, said that “The most brilliant analysis ever
done on a structural puzzle was surely the solution (1953) of the terramycin
problem.”
Why were they being searched for?
At that time, a gold rush was on to discover antibiotics from natural sources.
Hadn’t penicillin just been discovered?
Chlorotetracycline had advantages over the other antibiotics that were available at the
time (including penicillin) as it could be taken orally and was also effective against
both Gram-positive and Gram-negative bacteria. By that time, resistance to penicillin
had already been noted, so alternative antibiotics were a must.
HO CH3
H
NMe2
H
OH
NH2
OH
OH
O
OH
O
O
tetracycline
How do you make doxycycline?
CH3
OH
H
D
C
NMe2
H
OH
A
B
NH2
OH
OH
O
OH
O
O
doxycycline
In 2005, Andrew Myers’ group at Harvard University described an 18-step synthesis,
starting from benzoic acid.
H3C
N
CO2H
OCH3
TBSO
N
CH3
O
O
O
TBSO
H3C
CH3
N
N
O
TBSO
O
OBz
TBSO
OBz
O
O
H3C
N
BzO
CH3
CH3
O
H3C
N
CH3
LiOTf
O
O
N
CF3CO2H
N
OPh
HO
OH
TBSO
OBz
O
BocO
O
TBSO
O
OBz
O
O
BzO
CH3
O
H3C
N
CH3
CH3
CH3
H3C
N
OH
OH
O
N
HF, then
NH2
H2/Pd
BocO
O
OH
TBSO
O
OBz
OH
O
OH
OH
O
O
The benzoic acid molecule forms the basis of the B ring of the doxycycline, around
which the A, C and D rings are added by various ring-forming reactions. First the
benzoic acid undergoes microbial dihydroxylation, followed by further steps
including epoxidation and the introduction of protecting tert-butyldimethylsilyl
groups (TBS) to afford an enantiomerically-pure epoxyester. A deprotonated
dimethylamino substituted isoxazole is then added, subsequent ring closure in the
successive reactions with lithium triflate generating the A ring, and trifluoroacetic
acid removing a TBS group. The C and D rings were then added by means of a
coupling reaction with another carbanionic reagent via a Michael-Dieckmann
sequence. Removal of the protecting groups (TBS = tert-butyldimethylsilyl; BOC =
tert-butyloxycarbonyl, COtC4H9) afforded doxycycline, stereoselectively. The yield in
this virtuoso demonstration of synthetic organic chemistry was 8.3%.
How do tetracyclines work?
Tetracyclines inhibit bacterial protein synthesis. They bind to the 16S part of the 30S
subunit in the ribosome, and interfere with the binding of amino acylated tRNA,
stopping the messenger-RNA codon reading the t-RNA anticodon. This is a key step
of protein synthesis, and means that new aminoacids cannot be added to the nascent
polypeptide chain. This explains why tetracyclines are effective against a wide range
of both gram-positive and gram-negative bacteria.
So why don’t we hear more about them?
The tetracyclines are not used as widely as they once were, because of the emergence
of resistant strains of bacteria. In part, this is due to the use of small amounts of
antibiotics in animal feeds of animals such as pigs, chicken and cattle, in order to
control disease and promote growth.
Apart from doxycycline, several tetracyclines still find wide application. Many
members of the tetracycline family have been made by semisynthesis, using a
naturally produced molecule to provide the core, then modifying its structure. Among
the newer tetracyclines, tigecycline (Tygacil; 2005) is active against resistant bacteria
such as Staphylococcus aureus.
NMe2
NMe2
H
H
OH
O
NH2
N
H
OH
OH
NH
O
OH
O
O
tigecycline
Like other tetracyclines, minocycline is used as an oral antibiotic for acne, but in 2011
Canadian scientists carried out a screening of combinations of minocycline with other
drugs and showed that a combination of minocycline with the well-known antidiarrhoea drug loperamide was a potent antibacterial. Tests have not been carried out
on human yet, but it is possible that such combinations could give new life to
tetracyclines in medicine.
NMe2
NMe2
H
H
O
NH2
OH
OH
OH
O
O
OH
Minocycline
Recently Andrew Myers’ group have synthesised five-ring pentacyclines that show
promise against pathogens that are resistant to some other medications.
NMe2
H
H
OH
NH2
OH
OH
O
OH
O
OH
Pentacycline
But tetracyclines have actually been used for over 1500 years. It turns out that
tetracycline was present in ancient Nubian beer and contributed to low rates of
infectious disease.
I know that G- - - - - - - was good for you, but not Nubian beer!
The Nubian beer wasn’t like the present-day stuff; it was more like a syrupy gruel. 30
years ago, scientists at Emory University detected a green fluorescence when UV
light was shone on bones from Nubian skeletons, dating from between 350 and 550
AD. This indicated the presence of tetracycline.
Reproduced by permission of Professor George J. Armelagos.
It was found that the beer was made by fermenting grain which contained
streptomyces bacteria, found in soil. Further research indicated there were high levels
of tetracycline in the bones of even small children. The ancient Nubians recognised
the health effects of the beer and deliberately produced it, even if they did not know
about tetracycline.
Acknowledgements Thanks are due to Professor George Armelagos of Emory
University to reproduce an illustration, and to Professor James Anderson of UCL for
advice.
Bibliography: Chapman and Hall Combined Chemical Dictionary compounds code numbers: tetracycline BDQ00-F; chlorotetracycline CKR88-Y; oxytetracycline CLB98-G;
doxycycline BDT97-C; tigecycline KKB19-M; minocycline CKJ08-M (props,
bibliography)
General
A. Gringauz, Introduction to Medicinal Chemistry: How Drugs Act and Why, New
York, Wiley-Blackwell, 2nd edition, (1996), pp 243-247 (structure-activity
relationship)
M. Nelson. W. Hillen and R.A. Greenwald (eds), Tetracyclines in Biology, Chemistry
and Medicine, Basel, Birkhäuser Verlag, (2001).
G. L. Patrick, An Introduction to Medicinal Chemistry, 2nd edition, Oxford, OUP,
(2001), pp 425-426.
J. Mann, Life Saving Drugs: The Elusive Magic Bullet, Cambridge, RSC, (2004),
pp.70-71.
J. J. Li, Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We
Use, New York, OUP USA, (2006), pp 67-69.
E. J. Corey, B. Czako and N. Kürti, Molecules and Medicine, Hoboken, New Jersey,
(2007), p. 133.
K. C. Nicolaou and T. Montagnon, Molecules that changed the World, Weinheim,
Wiley VCH, (2008), pp 290-291
Reviews
M. L. Nelson, Ann. Rep. Med. Chem., (2002), 37, 105- 114.
L. B. Pickens and Y. Tang, Metab. Eng., (2009), 11, 69-75 (biosynth rev.)
M. O. Griffin, E. Fricovsky, G. Ceballos and F. Villarreal, Am. J. Physiol Cell
Physiol., (2010), 299, C539 - 548.
Synthesis of doxycycline
C. Khosla and Y. Tang, Science, (2005), 308, 367-368
M. G. Charest, C. D. Lerner, J. D. Brubaker, D. R. Siegel and A.G. Myers, Science,
(2005), 308, 395-398.
D. F. Taber, Organic Chemistry Highlights, November 7 2005, at: http://www.organic-chemistry.org/Highlights/2005/07November.shtm
Synthesis and biosynthesis of tetracyclines
F. A. Hochstein, C. R. Stephens, L. H. Conover, P. P. Regna, R. Pasternack, P.
Gordon, F. J. Pilgrim, K. J. Brunings and R. B. Woodward, J. Am. Chem. Soc.,
(1953), 75, 5455–5475 (structure of terramycin, oxytetracycline)
L. H. Conover, K. Butler, J. D. Johnston, J. J. Korst and R. B. Woodward, J. Am.
Chem. Soc., (1962), 84, 3222-3224 (total synth. of sancycline (6-demethyl-6deoxytetracycline))
H. Muxfeldt, G. Hardtmann, F. Kathawala, E. Vedejs and J. B. Mooberry, J. Am.
Chem. Soc., (1968), 90, 6534- 6536 (total synth. of terramycin)
J. D. Brubaker, D. R. Siegel and A.G. Myers, Org. Lett., (2007), 9, 3523-3525.
C. Sun, Q. Wang, J. D. Brubaker, P. M. Wright, C. D. Lerner, K. Noson, M. Charest,
D. R. Siegel, Y.-M. Wang and A. G. Myers, J. Am. Chem. Soc., (2008), 130, 1791317927.
C. Sun, D. Hunt, R. Clark, D. Lofland, W. O'Brien, L. Plamondon, and X.-Y. Xiao, J.
Med. Chem., (2011), 54, 3704–3731 (pentacyclin)
Means of action of tetracycline
D. E. Brodersen, W. M. Clemons, A. P. Carter, R. J. Morgan-Warren, B. T.
Wimberly and V. Ramakrishnan, Cell, (2000), 103, 1143-1154.
M. Pioletti, F. Schlünzen, J. Harms, R. Zarivach, M. Glühmann, H. Avila, A. Bashan,
H. Bartels, T. Auerbach, C. Jacobi, T. Hartsch, A. Yonath and F. Franceschi, EMBO
J., (2001), 20, 1829 – 1839. (cryst. struct. of tetracycline complex of the small
ribosomal subunit)
Tetracyclines in combinational therapy.
L. Principe, S. D'Arezzo, A. Capone, N. Petrosillo and P. Visca, Ann. Clin. Microbiol.
Antimicrob., (2009), 8, 18 – 27. (tigecycline)
L. Ejim, M. A. Farha, S. B Falconer, J. Wildenhain, B. K Coombes, M. Tyers, E. D.
Brown and G. D. Wright, Nature Chem. Biol., (2011), 7, 348-350 (minocycline).
Tetracycline in Nubian bones and beer.
E. J. Bassett, M. S. Keith, G. J. Armelagos, D. L. Martin and A. R. Villanueva,
Science, (1980), 209, 1532–1534.
G. J. Armelagos, Natural History, (2000), 109, 50-53.
G. J. Armelagos, K. Kolbacher, K. Collins, J. Cook and M. Krafeld-Daugbeny,
Tetracycline consumption in prehistory, in M. Nelson. W. Hillen and R.A. Greenwald
(eds), Tetracyclines in Biology, Chemistry and Medicine, Basel, Birkhauser Verlag,
(2001), pp 219-236.
M. L. Nelson, A. Dinardo, J. Hochberg and G. J. Armelagos, Amer. J. Phys.
Anthropol., (2010), 143, 151 – 154. (mass spec. characterization of tetracycline)
http://www.wired.com/wiredscience/2010/09/antibiotic-beer/ (summary)
Doxycycline
DOXYCYCLINE: AN OLD DRUG WITH A NEW ROLE IN IDIOPATHIC
PULMONARY FIBROSIS
GYANSHANKAR P. MISHRA AND JASMIN D. MULANI, Int. J. Pharma and
Bio, Sci., 2010, 1, pp 1-6.
Tetracycline (INN) ( /ˌtɛtrəˈsaɪkliːn/) is a broad-spectrum polyketide antibiotic
produced by the Streptomyces genus of Actinobacteria, indicated for use against many
bacterial infections. It is a protein synthesis inhibitor. It is commonly used to treat
acne today, and, more recently, rosacea, and played a historical role in reducing the
incidence of mortality because of cholera. It is marketed under the brand names
Sumycin, Terramycin, Tetracyn, and Panmycin, among others. Actisite is a threadlike fiber form, used in dental applications. It is also used to produce several
semisynthetic derivatives, which together are known as the tetracycline antibiotics.
Contents
[hide]
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1 Mechanism of action
2 History
3 Cautions, contraindications, side effects
4 Indications
5 Other uses
6 Cell culture
7 Notes
[edit] Mechanism of action
This section does not cite any references or sources.
Please help improve this article by adding citations to reliable sources. Unsourced material
may be challenged and removed. (January 2011)
Tetracyclines bind to the 30S subunit of microbial ribosomes. They inhibit protein
synthesis by blocking the attachment of charged aminoacyl-tRNA. Thus they prevent
introduction of new amino acids to the nascent peptide chain. The action is usually
inhibitory and reversible upon withdrawal of the drug. Resistance to the tetracyclines
results from changes in permeability of the microbial cell envelope. In susceptible
cells, the drug is concentrated from the environment and does not readily leave the
cell. In resistant cells, the drug is not actively transported into the cell or leaves it so
rapidly that inhibitory concentrations are not maintained. This is often plasmidcontrolled. Mammalian cells are not vulnerable to the effect of tetracyclines as these
contain no 30S ribosomal subunit and therefore do not actively concentrate the drug.
Tetracycline is also being used in recent years as a scar tissue remover. The
Tetracycline breaks down scar tissue and promotes healthy skin growth that causes a
semi-rapid normal skin tissue growth that makes any scars unnoticeable.
[edit] History
The tetracyclines are a large family of antibiotics that were discovered as natural
products by Benjamin Minge Duggar and first described in 1948.[1] Under
Yellapragada Subbarao, Benjamin Duggar made his discovery of the world's first
tetracycline antibiotic, Aureomycin, in 1945.
In 1950, Harvard Professor Robert Woodward determined the chemical structure of
Terramycin, the brand name for a member of the tetracycline family; the patent[2]
protection for its fermentation and production was also first issued in 1950. A
research team of seven scientists (Drs. K.J. Brunings, Francis A. Hochstein, C.R.
Stephens, L.H. Conover, Abraham Bavley, Richard Pasternack, and Peter P. Regna) at
Pfizer,[3][4] in collaboration with Woodward, participated in the two-year research
leading to the discovery.[5]
Nubian mummies studied in the 1990s were found to contain significant levels of
tetracycline; there is evidence that the beer brewed at the time could have been the
source.[6] Tetracycline sparked the development of many chemically altered
antibiotics, and in doing so has proved to be one of the most important discoveries
made in the field of antibiotics.[citation needed] It is used to treat many Gram-positive and
Gram-negative bacteria and some protozoa.[citation needed] It, like some other antibiotics,
is also used in the treatment of acne.[citation needed]
[edit] Cautions, contraindications, side effects
Are as those of the tetracycline antibiotics group:[citation needed]


Can stain developing teeth (even when taken by the mother during pregnancy)
Can cause permanent teeth discoloration (yellow-gray-brown); infancy and
childhood to eight years old
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








Inactivated by Ca2+ ion, not to be taken with milk, yogurt, and other dairy
products
Inactivated by aluminium, iron and zinc, not to be taken at the same time as
indigestion remedies
Inactivated by common antacids and over-the-counter heartburn medicines
Skin photosensitivity; exposure to the sun or intense light is not recommended
Drug-induced lupus, and hepatitis
Can induce microvesicular fatty liver.
Tinnitus
May interfere with methotrexate by displacing it from the various protein
binding sites
Can cause breathing complications as well as anaphylactic shock in some
individuals
Should be avoided during pregnancy as it may affect bone growth of the fetus
Passes into breast milk and is harmful to breast-fed infants, and should
therefore be avoided during breastfeeding if possible[7]
In 2010, the FDA added tetracycline to its Adverse Event Reporting System
(AERS).[8] The AERS contains a list of medications under investigation by the FDA
for potential safety issues. The list is published quarterly and available online. The
AERS cites a potential link between the use of tetracycline products and StevensJohnson syndrome, toxic epidermal necrolysis and erythema multiforme.[8]
[edit] Indications
It is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Q fever
(Coxiella), psittacosis and lymphogranuloma venereum (Chlamydia), and to eradicate
nasal carriage of meningococci. Tetracycline tablets were used in the plague outbreak
in India in 1992.[9]
Doxycycline is also one (of many) recommended drugs for chemoprophylatic
treatment of malaria in travels to areas of the world where malaria is endemic.[10]
[edit] Other uses
Since tetracycline is absorbed into bone, it is used as a marker of bone growth for
biopsies in humans. Tetracycline labeling is used to determine the amount of bone
growth within a certain period of time, usually a period of approximately 21 days.
Tetracycline is incorporated into mineralizing bone and can be detected by its
fluorescence.[11] In double tetracycline labeling, a second dose is given 11–14 days
after the first dose, and the amount of bone formed during that interval can be
calculated by measuring the distance between the two fluorescent labels.[12]
Tetracycline is also used as a biomarker in wildlife to detect consumption of
medicine- or vaccine-containing baits.[13]
In genetic engineering, tetracycline is used in transcriptional activation. Tetracycline
is also one of the antibiotics used to treat ulcers caused by bacterial infections. In
cancer research at Harvard Medical School, tetracycline has been used to reliably
cause regression of advanced stages of leukemia in mice, by placing it in their
drinking water.[14]
[edit] Cell culture
This section does not cite any references or sources.
Please help improve this article by adding citations to reliable sources. Unsourced material
may be challenged and removed. (January 2011)
Tetracycline is used in cell biology as selective agent in cell culture systems. It is
toxic to prokaryotic and eukaryotic cells and selects for cells harboring the bacterial
tetr gene, which encodes a 399-amino acid membrane-associated protein. This protein
actively exports tetracycline out of the cell, rendering cells harboring this gene more
resistant to the drug. The yellow crystalline powder can be dissolved in water
(20 mg/ml) or ethanol (5 mg/ml) and is routinely used at 10 mg/l in cell culture. In
cell culture at 37 °C (99 °F), it is stable for days, half-life ~24 hours.
[edit] Notes
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
^ Klajn, Rafal, Chemistry and chemical biology of tetracyclines, retrieved 20
June 2007.
^ U.S. Patent 2,516,080
^ [1]
^ "Scientists Discover Terramycin's Secret: Its Complex Structure".
http://pqasb.pqarchiver.com/djreprints/access/107482962.html?dids=107482962:1074
82962&FMT=ABS&FMTS=ABS:AI&type=historic&date=Jul+28%2C+1952&autho
r=&pub=Wall+Street+Journal&desc=Scientists+Discover+Terramycin's+Secret%3A
+Its+Complex+Structure&pqatl=google.
^ Hochstein, F. A.; Stephens, C. R.; Conover, L. H.; Regna, P. P.;
Pasternack, R.; Gordon, P. N.; Pilgrim, F. J.; Brunings, K. J. et al. (November 1953).
"The structure of terramycin". Journal of the American Chemical Society 75 (22):
5455–75. doi:10.1021/ja01118a001.
^ George Armelagos (May 2000). "Take Two Beers and Call Me in 1,600
Years - use of tetracycline by Nubians and Ancient Egyptians". American Museum of
Natural History.
http://www.findarticles.com/p/articles/mi_m1134/is_4_109/ai_62324477. Retrieved
2007-12-19.
^ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Retrieved
on June 19, 2009
^ a b FDA Adverse Events Reporting System Retrieved on January 14, 2011
^ Lippincott's Illustrated Reviews: Pharmacology, 4th ed. Harvery RA,
Champe, PC. Lippincott, Williams & Wilkins, 2009
^ Chapter 2 - Malaria - 2010 Yellow Book | CDC Travelers' Health
^ Mayton CA. Tetracycline labeling of bone
^ The Johns Hopkins Medical Institutions. > Tetracycline Labeling Last
updated January 8, 2001.
^ Olson CA, Mitchell KD, Werner PA (October 2000). "Bait ingestion by
free-ranging raccoons and nontarget species in an oral rabies vaccine field trial in
Florida". J. Wildl. Dis. 36 (4): 734–43. PMID 11085436.
http://www.jwildlifedis.org/cgi/reprint/36/4/734.
14.
^ William J. Cromie (February 10, 2000). "Researchers Switch Cancer Off
and On -- In Mice". http://news.harvard.edu/gazette/2000/02.10/leukemia.html.
Retrieved 2008-10-25
http://noisewiki.com/wiki/images/cache/7/74/File%253ATwinTowers%252Ejpg.html