Novel synthesis of highly cytotoxic cyclopropabenzindoles for incorporation into a prodrug system targeting prostate tumours

  • Michael Kenny

Student thesis: Doctoral ThesisPhD


Prostate cancer will affect one in eight men during their lifetime and is the fifth leading cause of cancer related deaths in men. Conventional treatments for prostate cancer include androgen-deprivation therapy, however, most men treated with androgen-deprivation therapy progress to hormone-refractory prostate cancer. There are currently no curative treatments for hormone-refractory prostate cancer. Cyclopropabenzindoles (CBI) are more biologically potent and synthetically accessible analogues of the cyclopropapyrroloindole (CPI) anti-tumour antibiotics, such as duocarmycin-SA and CC1065. Seco-amino-CBIs can be incorporated into a polymeric prodrug system that will release the seco-amino-CBIs at the site of tumour selectively. The polymeric prodrug system consists of linear polyethyleneglycol (20 KDa) bound to a PSA-cleavable linker peptide to which the seco-amino-CBI is attached. The prodrug has two modes of selectivity: activation by PSA and the EPR effect. The synthesis of a range of seco-amino-CBI compounds was performed in order to investigate the structure- activity relationship surrounding the non-alkylating DNA minor-groove binding subunit. A novel synthetic route was developed to bypass issues surrounding the required orthogonal protection of two amine groups. This route provided access to a range of seco-nitro-CBIs that were further investigated as hypoxia-activated prodrugs. Biological evaluation of the seco- nitro-CBIs and seco-amino-CBIs was investigated through DNA-melting assays which confirmed the ability of the seco-amino-CBIs to bind covalently to DNA. MTS-assays were carried out to evaluate the relative cytotoxicity’s of the range of seco-nitro-CBIs and seco- amino-CBIs. Novel compound (5-amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indol-3- yl)(5-hydroxy-1H-indol-2-yl)methanone showed exquisite potency, with a determined IC50 value of 1.5 nM against PC3 cells. MTS-assays performed under hypoxic conditions allowed the investigation into the suitability of the seco-nitro-CBIs as hypoxia-activated prodrugs. (1- (chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-3-yl)(5-hydroxy-1H-indol-2- yl)methanone exhibited a hypoxia-cytotoxicity ratio of 2.34.
Date of Award3 Apr 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorMatthew Lloyd (Supervisor), Andy Thompson (Supervisor) & Michael Threadgill (Supervisor)

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