Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Twum, Elvis A.; Nathubhai, Amit; Wood, Pauline J.; Lloyd, Matthew D.; Thompson, Andrew S.; Threadgill, Michael D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3481
• Page End: 3489
• Publication Date: 2015-07-01
• Subjects: CBI -- Prodrug -- TEMPO -- Amino-CBI -- Cytotoxin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.034
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2, 3-dihydrobenzo[ e ]indoles (5-OH- seco -CBIs). Corresponding 5-NH2 - seco -CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2 - seco -CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1, 3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5- exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2 - seco -CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (Δ T m = 13 °C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM).