Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity

摘要

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 center dot center dot center dot N2-H2 center dot center dot center dot 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 center dot center dot center dot O1 and O4-H center dot center dot center dot 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 Ag(2)cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)center dot 2H(2)O (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 center dot center dot center dot O, O-H center dot center dot center dot Cl, N-H center dot center dot center dot Cl, and N-H center dot center dot center dot 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 mu M was found against the noncancer cell line HEK293.