Biomedical Engineering Reference
In-Depth Information
25.5.1.2 Tetracyclines
The i rst tetracycline, chlortetracycline, was discovered in 1948 in a culture of
Streptomyces
aureofaciens
. Oxytetracycline was isolated somewhat later (1950) from
Streptomyces rimosus
.
The structure was studied in the laboratories of Lederle (Boothe et al.) and Pi zer (Hochstein et al.)
in collaboration with Woodward at Harvard University. The full structure was published in 1952
but complete stereochemistry was obtained later from x-ray diffraction analysis. During these
studies, it was found that the removal of chlorine from chlortetracycline by hydrogenolysis led
to an active product, tetracycline. In other laboratories, it was shown that tetracycline could be
produced by fermentation of a medium poor in chloride using an appropriate strain, e.g.,
S. alboniger,
S. viridifaciens
,
etc.
The tetracyclines derive their name from the tetracyclic ring system, which is octahydronaph-
thacene. They have three ionizable groups, on C
3
, C
4
, and the dihydroxy ketone system (C
10
-C
12
).
The tetracyclines are often used in the form of the hydrochloride, but the tetracycline bases are also
used. The C
4
. dimethylamino-group may epimerize and these epimers are almost inactive. At pH
values between 4 and 7, mixtures of normal and epitetracycline are formed.
In acid medium, the C
6
hydroxy group and C
5
hydrogen are removed in the form of water
and anhydrotetracyclines are found. For this reason demeclocyline, which has a C
6
secondary
hydroxyl group instead of a tertiary one, is more stable. This product was obtained in 1957
using a mutant strain of
S. aureofaciens
. Chemical manipulations of oxytetracycline led to
the production of metacycline. Hydrogenation of metacycline under suitable conditions, gave
doxycycline. It should be noted that the C
6
methyl group should have the a-coni guration as
in oxytetracycline, because the C
6
epimer is less active. Doxycycline is very stable (no C
6
-OH
group) and has a high lipophilic character. It is more completely absorbed after oral administration.
Minocycline was described in 1972 and is prepared by the chemical treatment of 6-deoxy-
6-demethyltetracycline.
The tetracyclines are true broad-spectrum antibiotics. They are active against a wide range of
Gram-positive and Gram-negative bacteria, spirochetes, mycoplasmas, rickettsiae, and chlamydia.
The
in vitro
activities of the different tetracyclines are very similar. Only the greater activity of
minocycline against some Gram-positive bacteria like staphylococci and streptococci should be
noted (Figure 25.14).
R
1
R
2
R
3
H
H
4
H
(
3
)
2
H
OH
CONH
2
OH
HO
O
OH
O
R
2
R
1
R
3
R
4
H
OH
CH
3
H
Tetracycline
Cl
OH
CH
3
H
Chlortetracycline
H
OH
CH
3
OH
Oxytetracycline
Cl
OH
H
H
Demeclocycline
H
CH
2
OH
Metacycline
H
H
CH
3
OH
Doxycycline
N(CH
3
)
2
H
H
H
Minocycline
FIGURE 25.14
Tet r a cycl i nes.
