title: Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems.
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 (ΔTm=13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50=18nM).
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Elvis A
authors.initials: EA
authors.lastname: Twum
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathubhai
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Wood
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. Electronic address: m.d.threadgill@bath.ac.uk.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000081:Acetamides; D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000737:chemistry; D003500:Cyclization; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005463:Fluoroacetates; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry; D009691:Nucleic Acid Denaturation; D011355:Prodrugs; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D018906:Antineoplastic Agents, Alkylating; D003497:Cyclic N-Oxides; D003521:Cyclopropanes; D004273:DNA, Neoplasm; D005463:Fluoroacetates; D007211:Indoles; D009281:Naphthalenes; D011355:Prodrugs; C030688:trifluoroacetamide; C003959:TEMPO
keywords: Amino-CBI; CBI; Cytotoxin; Prodrug; TEMPO