Development of Prodrugs to Deliver Super-Potent Drugs to Prostate Tumors

  • Elvis Twum

Student thesis: Doctoral ThesisPhD


Conventional treatments for prostate cancer have significant limitations making it difficult to control the disease. Cyclopropabenzindoles (CBI) are more biologically potent, stable and synthetically accessible analogues of cyclopropapyrroloindole (CPI) anti-tumour antibiotics, such as duocarmycin-SA and CC1065. A polymeric prodrug carrying a CBI drug attached to the polymeric backbone through a PSA cleavable linker peptide has two modes of selectivity: activation by PSA and the EPR effect. To synthesise a 5-amino-seco-CBI analogue, 2,4-dinitronaphthalen- 1-ol gave di-Boc-1-iodonaphthalene-2,4-diamine in five steps (triflation, SNAr displacement with iodide, reduction (loss of iodine), protection and restoration of the iodine. For the amino-seco-CBI, it was important to discriminate between N2 and N4. Acidic removal of the Boc-group(s) resulted in deiodination. NMR investigations showed an unexpected Wheland-like cationic intermediate. N3 of naphthalene-1,3-diamine was selectively trifluoroacetylated and N1 was masked with Boc. Electrophilic iodination gave an orthogonally protected 1-iodonaphthalene-2,4-diamine. Allylation at the trifluoroacetamide was followed by free radical cyclisation with TEMPO trap. Removal of the trifluoroacetyl group allowed coupling to 5-(2-(dimethylamino)ethoxy)-1H-indole-2-carboxylic acid. Reductive removal of 2,2,6,6-tetramethylpiperidine, substitution of the exposed hydroxy group with chloride and removal of the Boc-group gave the amino-seco-CBI drug, 5-amino-1-chloromethyl-3-(5-(2-dimethylaminoethoxy)indole-2-carbonyl)-2,3-dihydro-1H-benz[e]indole. A DNA-melting assay confirmed that it binds very strongly to dsDNA causing a 13 deg. C increase in melting temperature. The drug was a highly potent cytotoxin in vitro, with IC50 = 18 nM against LNCaP prostate cancer cells. The polymeric prodrug system involved the synthesis of the pentapeptide SSKLQ. The amide side chain of glutamine can be masked as the nitrile and this can be quantitatively hydrated to the γ-carboxamide of L-Gln with hydroperoxide. The pentapeptide was coupled to 4-methoxynaphthalen-1-amine and to poly(ethylene glycol) as a model polymeric prodrug system. Efficient release of the model drug from the polymeric prodrug by PSA will allow this polymeric prodrug system to be adopted for the synthesised amino-seco-CBI drug.
Date of Award5 Nov 2013
Original languageEnglish
Awarding Institution
  • University of Bath
SponsorsProstate Cancer UK
SupervisorMichael Threadgill (Supervisor), Andrew Thompson (Supervisor) & Matthew Lloyd (Supervisor)


  • duocarmycin
  • CC-1065
  • cyclopropabenzindole
  • cyclopropapyrroloindole
  • ant-tumour
  • cancer
  • prostate
  • peptide
  • prodrugs
  • EPR
  • polymer

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