title: Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity.
abstract: 3,7-Diallyl-bispidin-9-one (6) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]nonan-9-one) is converted to N-unsubstituted spiro[bispidin-9,2'-[1,3]dioxolane] (12; 35%). The ketal crystallizes in the forms of anhydrous 12a and the dihydrate 12b. The molecules in anhydrous 12a are linked to each other, forming N1-H1···N2-H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate 12b, the ketal molecules are connected to a central string of water molecules by O3-H···O1 and O4-H···N1 hydrogen bonds, but not to themselves. Reaction of 12 with (1,5-hexadiene)PtCl2 affords almost quantitatively spiro[bispidin-9,2'-[1,3]dioxolane]PtCl2 (13). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)PtCl2 (14; 85%). Compound 14 reacts with Ag2cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)·2H2O (15b), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)Pt(cbdca) (15a). Similarly, anhydrous (bispidin-9,9-diol)Pt(oxalate) (16) is obtained. Crystal structures of 14 and 15b reveal association by various forms of O-H···O, O-H···Cl, N-H···Cl, and N-H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes 14-16, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of 14-16 up to 316 μM was found against the noncancer cell line HEK293.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Huiling
authors.initials: H
authors.lastname: Cui
authors.affiliation: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Goddard
authors.affiliation: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
authors.forename: Klaus-Richard
authors.initials: KR
authors.lastname: Pörschke
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D016190:Carboplatin / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C074973:bispidinol; D016190:Carboplatin; D002945:Cisplatin