Camptothecin, (CPT) is a pentacyclic alkaloid isolated for the first time from the
Chinese tree Camptotheca acuminata, and which has soon attracted the attention of
medicinal chemists and pharmacologists due to its promising anti-cancer activity
against the most aggressive histo-types. So far, most of the synthesized camptothecin
analogues are A and B ring modified compounds, which have been prepared via
synthetic or semi-synthetic routes. To the best of our knowledge, a very limited number
of C, D, or E ring modified analogues of CPT have been reported; moreover, the few
derivatives known from the literature showed a reduced or no biological activity.
This dissertation presents synthetic studies on camptothecin new derivatives along with
the development of a new and general semi-synthetic methodology to obtain a large
variety of analogues.
We report here the semi-synthesis of a new family of 5-substituted CPT's, along with
their biological activity evaluation, which will be compared with reference compounds.
The use of carrier-linked prodrugs has emerged as a useful strategy to overcome some
of the drawbacks related with the use of the parent drug, such as low solubility,
membrane permeability properties, low oral absorption, instability, toxicity, and nontargeting.
Herein we report CPT-prodrugs synthesized via ring opening of the lactone
moiety as 17-O-acyl camptothecin tripartate conjugates, which bear a polyamine side
chain with different architectures, as the carriers.
Moreover, we found that the replacement of the oxygen atom with sulphur on the
piridone D-ring, dramatically improves the potency of the novel 16a-thio-camptothecin
derivatives, opening new possibilities in the modelling of this class of compounds.
| Identifer | oai:union.ndltd.org:unibo.it/oai:amsdottorato.cib.unibo.it:1050 |
| Date | 16 April 2008 |
| Creators | Samorì, Cristian <1976> |
| Contributors | Ricci, Alfredo |
| Publisher | Alma Mater Studiorum - Università di Bologna |
| Source Sets | Università di Bologna |
| Language | Italian |
| Detected Language | English |
| Type | Doctoral Thesis, PeerReviewed |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
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