THE CHEMISTRY AND BIOLOGY OF VANCOMYCIN AND OTHER GLYCOPEPTIDE ANTIBIOTIC DERIVATIVES - Medicinal Chemistry of Bioactive Natural Products - page 37

methods, partial structures were determined. 13 Paralleled crystallization experi-
ments yielded x-ray structures of antibiotically inactive CDP-1, a degradation pro-
duct of vancomycin. 14 The final and commonly accepted structures were published
by Williamson and Williams 15 and Harris and Harris. 16 In 1995, Sheldrick et al.
presented the first x-ray structure of a naturally occuring glycopeptide antibiotic,
balhimycin (Scheme 2-1). 17 On the basis of these contributions, the structures of
many other glycopeptides have been elucidated.

2.2 CLASSIFICATION OF GLYCOPEPTIDE ANTIBIOTICS

The high structural diversity within the glycopeptide family led to a classification
into five subtypes (Scheme 2-2). Types I-IV show antibacterial activity, whereas
type V shows antiviral activity, e.g., against the human immunodeficiency
virus (HIV). 18,19 The basic structural motif of types I-IV are three side-chain cycli-
zations of the aromatic amino acids of the heptapeptide backbone. These ring
systems are called AB-ring (biaryl) and C-O-D- and D-O-E-rings (diarylethers),
respectively. They are formed by cross-linking of the non-proteinogenic amino
acids b-hydroxytyrosine/tyrosine (Hty/Tyr), 4-hydroxyphenylglycine (Hpg), and
3,5-dihydroxyphenylglycine (Dpg).
From the aglycon portion of glycopeptide antibiotics, the amino acids in posi-
tions 1 and 3 are the criterion for the classification into types I-III. The vancomy-
cin-type (type I) glycopeptides have aliphatic amino acids in postions 1 and 3. In
contrast, the actinoidin-type (type II) glycopeptides have aromatic amino acids in
these positions, which are linked in the ristocetin A-type (type III) by one arylether
bond. This additional ring system is commonly assigned as the F-O-G-ring. The
rings of the teicoplanin-type (type IV) correspond to those of the ristocetin
A-type. However, the classification of teicoplanin as another subtype is based on
the acylation of an aminosugar with a fatty acid. Other structural features, e.g.,
the glycosylation pattern, the halogenation pattern, and the number of N-terminal
methyl groups vary widely within each subtype.
The type-V glycopeptide antibiotics with complestatin or chloropeptin as repre-
sentatives show no antibacterial activity. Instead, the inhibition of binding of viral
glycoprotein gp120 to cellular CD4-receptors was found. 19 Characteristic features
for this subclass are a DE-biaryl ring, which is formed by 4-hydroxyphenylglycine
(AA4) and tryptophan (AA2).
To highlight the structural features of glycopeptides in more detail, in Scheme
2-3, representatively the structure of vancomycin is shown. The glycopeptide con-
sists of a heptapeptide backbone with the sequence (R) 1 MeLeu-(2R,3R) 2 Cht-(S) 3
Asn-(R) 4 Hpg-(R) 5 Hpg-(2S,3R) 6 Cht-(S) 7 Dpg. Vancomycin has a total number of
18 stereocenters, with 9 stereocenters located in the aglycon and the remaining
stereocenters located in the carbohydrate residues. The AB-ring formed by 5 Hpg
and 7 Dpg is an atropoisomer with axial chirality. The C-O-D- and D-O-E-rings formed
by 2 Cht, 4 Hpg, and 6 Cht have planar chirality. The b-hydroxy groups of 2 Cht and
6 Cht are in anti-position to the chorine substituents attached to the aromatic rings.