Chemistry Reference
In-Depth Information
Camptothecin (CPT) is a cytotoxic, poorly water-soluble polycyclic quinoline
alkaloid that inhibits the DNA enzyme topoisomerase I (topo I). CPT binds to topo I
and causes DNA damage, which results in apoptosis. The search for newdrug delivery
systems for a selective chemotherapy lead to several articles by Shabat and coworkers.
It first started from the synthesis of a CPT-conjugate prodrug with a self-immolative
linker activated by an antibody catalysis [187] or an enzyme [197]. Penicillin-G-
amidase or catalytic antibody 38C2 triggered the release of CPT by hydrolysis of a
carbamate function. Cell growth inhibition assays indicated up to a 2250-fold
decrease in toxicity for the prodrug relative to the drug.
As a comparison to a dendritic prodrug, here is a description of a HPMA (N-(2-
hydroxypropyl)-methacrylamide) copolymer with some grafted molecular platforms
comprising a drug (CPT), a trigger site, and a targeting ligand (Scheme 13.8) [196e].
A self-immolative second-generation dendritic prodrug incorporating CPT, PEG
chains, and some cleavable units were synthesized with carbamate functional groups.
The latter PEG chains were installed via click chemistry. They helped in decreasing
the hydrophobic properties and avoided aggregates formation. The cleavage of the
dendrimer led to the release of CPT after an enzymatic triggering by penicillin-G-
amidase [231].
Paclitaxel (Taxol)
AcO
O
OH
O
Ph
O
O
N
H
Ph
H
OH
O
HO
BzO AcO
Taxol
Preliminary studies on the cascade disintegration of elongated cleavable units were
achieved by de Groot et al. for releasing paclitaxel or DOX [134]. In this article, they
used an enzymatic triggering from human plasmin to cleave some linear prodrugs via
a double or a triple benzyloxycarbonyl spacer incorporating carbonate or carbamate
functions, and a combination with a bisamine cyclization spacer. It was shown that the
catalytic rates of the degradation were faster for a double or a triple spacer compared
to a single one. Dendrimers were not used in this study but prepared the groundwork
for a subsequent publication on dendrimer-drug conjugates. Similarly, another work
described the test of many prodrugs for their toxicity against many human tumor cell
lines. They could release paclitaxel after a bioreductive activation from nitro- or
azido-benzene derivatives and a carbonate linker [232].
de Groot et al. introduced some “cascade-release dendrimers” liberating paclitaxel
(taxol) with an amazing long range self-elimination chemical adaptor unit (a double
1,8-elimination). A reduction of a nitro to an amino function served as a redox trigger
to release two taxol molecules. This concept was extended to a higher generation
dendrimer releasing simultaneously four molecules of paclitaxel (Scheme 13.9)
[198b].
