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Synthesis of new 5-fluorouracil photosensitiser conjugates for use as prodrugs in the photodynamic therapy for cancer

Gray, Ian J. (2005) Synthesis of new 5-fluorouracil photosensitiser conjugates for use as prodrugs in the photodynamic therapy for cancer. PhD thesis, Dublin City University.

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A major limitation to cancer chemotherapy is the non-selectivity of the drug. One such drug that is used extensively to combat cancer is the pyrimidine derivative 5- fluorouracil (5-FU). However, its associated high toxicity and side effects has limited its clinical use. This in turn has challenged chemists to explore 5-FU prodrug derivatives in order to find a selective, non-toxic form. Although libraries of 5-FU prodrugs have been reported, selectivity still remains a problem and needs improvement. It was therefore our goal to try and improve 5-FU selectivity by designing a 5-FU prodrug that could be selectively delivered to the cancerous tissue where it could be activated. To achieve this we designed a 5-FU produg based on the general tumour activated prodrug (TAP) model concept i.e. triggers, linker and effector. It is known that nitro-aromatic moieties can be reduced by the hypoxic conditions associated with tumour cells hence, we can use these moieties as triggers to activate the 5-FU prodrug. Seven such compounds were synthesised and incubated with 4T1 cancer cell lines for 72 hrs, however only two of the synthesised compounds (52) and (53) showed significant increase in cytotoxicity under hypoxic conditions, thus indicating that activation by endogenous one-electron reductases was occurring. Photosensitisers used in photodynamic therapy (PDT) have been found to selectively accumulate in the cellular organelles of cancerous tissue. By exploiting this phenomena we coupled 5-FURD and the four synthesised nitro-5-FURD prodrugs to the photosensitiser dihydroxysilicon phthalocyanine. This in turn generated the five novel Bis(5-fluorouridine) phthalocyaninosilicon derivatives, thus allowing the photosensitiser to selectively carry the nitro-aromatic-5-FURD prodrug to the cancerous tissue, where the 5-FURD prodrug is activated thus releasing the 5-FU. However, this not only allows for the selective delivery of the 5-FU prodrug but generates a third generation photosensitiser that can be used in PDT application. However, the tumour reduction conditions may not be suitable for optimal activation of our nitro-aromatic prodrugs via the nitroreductase enzymes in the “dark”, we therefore propose two alternative possibilities for activation via (1) the action of gene directed enzyme prodrug therapy (GDEPT) and E.coli or (2) activation through the consequence of oxidative stress on the cell via the release of excess cellular reductase. It was found that of eleven 5-FU prodrugs tested on the SW480 and 4T1 cancer cell lines two (59) and (58) gave similar IC50 values as that for the 5-FU drug and that three of the prodrugs (53), (59) and (69) gave lower anti-invasion activity then the 5-FU drug. We report the synthesis of a novel prodrug 2’,3’-isopropylidene-5,-0-((-4” S,5” R)-Nacetyl- 2’ ’ ,2” -dimethyl-4 ’ ’ -phenyl-1 ” ,3 ” -oxazolidine-5 ’ ’ -carboxylate)-fluorouridine 102). This design incorporates a lipophillic handle coupled to 5-fluorouridine. This compound was tested on SW480 and 4T1 cancer cell lines, however no cell death was observed at the concentrations used, instead growth inducement behaviour was exhibited. Following a SAR study this was attributed to (1) 5-fluorouridine being in the protected form of 2,3-isoprpoylidene-5-fluorouridine, thus preventing the formation of 5-fluorouracil metabolites and (2) the presence of the lipophillic ester slowing down its activation.

Item Type:Thesis (PhD)
Date of Award:2005
Supervisor(s):Nolan, Kieran
Uncontrolled Keywords:chemotherapy; selectivity; cytotoxity; photodynamic therapy; PDT
Subjects:Physical Sciences > Photochemistry
Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:17304
Deposited On:28 Aug 2012 14:37 by Fran Callaghan. Last Modified 28 Aug 2012 14:37

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