Synthesis and Biological Evaluation of Novel Anti-Cancer Agents

Henderson, Nicola Dione (1994) Synthesis and Biological Evaluation of Novel Anti-Cancer Agents. PhD thesis, University of Glasgow.

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Bioreducible antitumour agents are prodrugs which are intended to be inactive in their own right, but are able to undergo metabolic reduction to produce toxic species which can damage biomolecules. This reduction may occur readily in solid tumours due to two factors which are unique to them, a) tumour hypoxia; and b) the expression of high levels of reductase enzymes. Each of these factors can promote specific cytotoxicity to the tumour and in principle could create a selective antitumour agent. A series of N-oxides of heterocyclic aliphatic amines was prepared for evaluation as bioreducible drugs. N-oxides (A) of cis- and trans-2,6-disubstituted N-methyl-piperidine were prepared with X equal to carbamate or halogen. The free bases were designed to be bifunctional alkylating agents via aziridine ion formation. The cis-isomer was synthesised by hydrogenation of a derivative of dipicolinic acid followed by reduction to produce the diol from which the leaving groups were attatched. The trans-isomer was synthesised by ring closure of a pimelic acid derivative with methylamine followed by acidic epimerisation, from which the diol was obtained and derivatised. In total, 22 mostly novel compounds were synthesised and tested against two human colon carcinoma cell lines, HT 29 and BE cells under oxic and hypoxic conditions. HT 29 cells produce high amounts of DT-diaphorase which is a reductase enzyme that favours a 2e- reduction pathway, whilst BE cells contains no DT-diaphorase. IC50 values were also measured for selected compounds. The results showed that the free bases are toxic against both cell lines and the N-oxides are nontoxic. This suggested that the mono-N-oxides were not reduced under hypoxic conditions which implies that the reduction potentials of the compounds are not in the correct range for cellular reductants. Bis-N-oxides (B) of 1,4-disubstituted piperazines were also prepared and 10 mainly novel compounds were synthesised and tested in the same biological systems. These N-oxides also did not give any evidence of being reduced under hypoxic conditions but did have reduced toxicity in comparison to the free bases. IC50 values were measured for these compounds and the values indicated that the free bases were up to 1000-fold more toxic than the corresponding bis-N-oxides. In attempts to modify the reduction potentials of the piperidine N-oxides, a series of bis-piperidine-bis-N-oxides (C) of varying carbon chain length were prepared by a general route by linking two methyl pipecolinate molecules with a selection of diacid chlorides followed by reduction and introduction of the X group. 20 predominantly novel compounds were prepared and evaluated for toxicity and selectivity. There was little evidence of hypoxic/oxic selectivity by the N-oxides although their toxicity was substantially reduced compared to the free bases. The toxicity of the free bases did seem affected by the length of the carbon chain, and the compounds with a four carbon chain were most toxic by several orders of magnitude. (C) Cobalt is known to form stable octahedral Co(III) complexes with a range of aliphatic amines and the reduction potentials of such complexes fall within an reduction results in release of the ligands and it has been suggested that this may be incorporated into the design of novel bioreducible antitumour agents. A range of diamines, triamines and tetraamines with alkylating functionality were synthesised and complexed to Co(III). The polyamines were formed by a general route starting with amino acids and using mixed anhydride methodology to attach the nitrogen mustard functionality. The amines were obtained as hydrochloride salts and IC50 values were obtained. All were reasonably toxic, the most toxic having IC50 values in the J, molar region. Five cobalt complexes, such as D, were isolated and tested for oxic/hypoxic selectivity, two of which had been synthesised before. Of these, two showed promising selectivity, exhibiting greater toxicity under hypoxic conditions than under oxic conditions, although further testing is required.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David J Robins
Keywords: Pharmacology
Date of Award: 1994
Depositing User: Enlighten Team
Unique ID: glathesis:1994-74969
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 14:50
Last Modified: 27 Sep 2019 14:50

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