Chemistry Reference
In-Depth Information
O
HO
NH
O
CH
3
O
CH
3
CH
3
-S-S-S
I
O
OCH
3
S
O
CH
3
O
H
HN
O
OCH
3
OH
O
HO
OCH
3
O
O
CH
3
CH
3
CH
2
HO
O
OCH
3
N
OH
H
OCH
3
Figure 5.1
Calicheamicin g
1
I
. g-Calicheamicin is the parent of this class of unusually
complex natural products. Unique are the methyl trisulfide, the three
sugar units closest to the bicyclic core, the per-substituted aromatic ring
containing iodine, and, especially,
the embedded enediyne that
is
responsible for its ability to cleave DNA.
Studies have shown that it prefers to bind to DNA sequences that have sucient
flexibility to bend slightly and widen the minor grove to accommodate binding.
8
The calicheamicin headpiece has an unusual enediyne unit that is kept stable
by a bicyclic framework containing a bridgehead alkene. This bridgehead alkene
limits the flexibility of the enediyne and does not allow it to undergo its normal
mode of reaction, Bergman cyclization to a diradical. However, reduction of the
appended methyl trisulfide, whether chemically or biologically, leads to an
intramolecular Michael reaction that removes the constraining bridgehead
alkene (Figure 5.2). This then allows the Bergman cyclization to occur with an
estimated half-life of 4.5 s.
9
When this diradical is situated in the minor grove of
DNA, where calicheamicin prefers to bind, it rapidly abstracts hydrogens from
opposite strands of the deoxyriboses, resulting in damage to both strands of
DNA simultaneously.
10
The double-stranded nature of the DNA damage is at
least in part responsible for the extreme potency of the calicheamicins. Such
potency is important for conjugates, as the limited amount that can be inter-
nalized by the available antigen needs to constitute a lethal dose.
Previous work with the anti-PEM antibody CTM01 showed the feasibility of
making conjugates of the calicheamicins.
11
The maximum therapeutic window
for these initial conjugates was obtained with derivatives of calicheamicin that
contained an amino sugar modified by acetylation (N-acetyl-g-calicheamicin)
and that contained a stabilized dimethyl disulfide instead of the naturally
occurring trisulfide. It is unknown why the acylation (or removal) of the amino
sugar is beneficial. A poorly understood chemical or biological role of the basic
nitrogen, reduction of the potency of the conjugate to a level that spares non-
target cells that take up small amounts of conjugate non-specifically, or the
ability to increase the dose of the conjugate to an amount that allows for better
pharmacokinetics (PK) are three possibilities.
Aside from the antibody and the cytotoxic agent, ADCs contain a linker that
attaches these components. The linker needs to be stable in circulation for
extended periods of time, but the ADC needs to be cleaved intracellularly,
Search WWH ::
Custom Search