title: Synthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumour agents.
abstract: We are seeking to develop more effective bifunctional alkylating agents as antitumour agents. We previously synthesized conformationally restricted nitrogen mustards containing one piperidine ring, then bispiperidine derivatives were designed and prepared with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. A bispiperidine with the shortest bridge of two carbon atoms was the most reactive bifunctional alkylating agent. In order to extend this work and investigate the effects of a change in the size of the heterocyclic systems, new bispyrrolidine salts 17-23 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-8 carbon atoms were synthesized from L-proline so that only the LL-enantiomers were produced. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. All of the bispyrrolidines were efficient cross-linkers of naked DNA apart from those with three-carbon (18) and four-carbon (19) bridges, in contrast to the results with the bispiperidines. A piperazine derivative 24 with two potential alkylating sites was also shown to be an efficient cross-linker, as was an alicyclic compound 25 with six carbon atoms between the two alkylating sites. Compounds 26 and 30 with an extra carbon atom between the nitrogen and the leaving group were not cross-linkers, as expected if aziridinium ion formation is crucial for cross-linking ability. The preformed aziridine 27 with a further alkylating site was an efficient cross-linker. Compounds 28-29 with only one potential alkylating centre were not cross-linkers of DNA. None of the compounds, however, produced significant cytotoxicity in human tumour cells in vitro.
authors.affiliation: Department of Chemistry, University of Glasgow, UK.
authors.forename: F M
authors.initials: FM
authors.lastname: Anderson
authors.forename: C C
authors.initials: CC
authors.lastname: O'Hare
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: D J
authors.initials: DJ
authors.lastname: Robins
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D020014:K562 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D007202:Indicators and Reagents; D011759:Pyrrolidines; D004247:DNA