Casely-Hayford, Maxwell Aku;
(2004)
Chemical synthesis and biological evaluation of potential anti-cancer agents based on the azinomycins.
Doctoral thesis (Ph.D.), University College London.
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Abstract
Azinomycins A 1 and B 2 isolated from the culture broths of Streptomyces griseofuscus S42227, exhibit potent in vitro cytotoxic activity and significant in vivo antitumour activity. The compounds contain two electrophilic functional groups - an epoxide and an aziridine residue - that react with nucleophilic sites in duplex DNA to form cross-links at 5'-dGNT and 5'-dGNC sequences. Although the aziridine functionality is required for cross-linking, the azinomycin metabolite (2S,3S)-3,4- epoxy-2-(3-methoxy-5-methyl-1-naphthoyloxy)-3-methylbutanamide containing an intact epoxide but devoid of the 1-aza-bicyclo[3.1.0]hexane ring system retains significant biological activity (IC50 in P388 murine leukaemia = 0.0012 μg/ml) comparable to agents such as cisplatin and mitomycin C. The natural product possesses (2S, 3S) stereochemistry. All the four diastereoisomers of 3,4-epoxy-2-(3- methoxy-5-methyl-l-naphthoyloxy)-3-methylbutanamide were synthesised to evaluate how the nature of stereochemistry influences cytotoxicity and DNA binding ability. The synthesis involved Sharpless asymmetric dihydroxylation of benzyl 3- methylbut-2-enoate using AD-mix-α or AD-mix-β to give a diol with (R) or (S) stereochemistry respectively. The (R) and (S) diols were converted into the four stereoisomers of benzyl 3,4-epoxy-2-hydroxy-3-methylbutanoate, coupled to the chromophore ethyl 3-methoxy-5-methyl-1-naphthoic acid and further converted to the azinomycin analogue (2S,3S)-3 and its isomers. These compounds together with other analogues containing modifications to the chromophore were investigated for cytotoxic activity. Their mode of action was investigated by studying their effect on the electrophoretic mobility of supercoiled plasmid DNA. Analogues with DNA cross-linking ability were designed and synthesised from 1-(2-aminoethyl)-piperidin-3-ol and 3,4-epoxy-2-(3-methoxy-5-methyl-1-naphthoyloxy)-3-methylbutanoic acid involving Boc-protection of the terminal primary amine, mesylation of the secondary hydroxyl group and transformation of this functionality to the chloro compound. Subsequent deprotection of the Boc-group and coupling to the left hand portion gave a series of piperidine-based analogues. These compounds were tested in the NCI 60 cell line panel and their mode of binding investigated using agarose gel DNA cross- linking and unwinding assays. Totally synthetic analogues with properties useful in the design of bioreductive and biooxidative prodrugs were synthesised by coupling the piperidine analogue 124 or the allylic alcohol 29 to the naphthoic acid chloride 94.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Chemical synthesis and biological evaluation of potential anti-cancer agents based on the azinomycins. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis Digitised by Proquest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10122066 |
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