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.

Ni(II), Pd(II), and Pt(II) Complexes of the Hedgehog Pathway Inhibitor GANT61-D

“…Selected bond lengths and bond angles around the Pt­(II) center can be seen in Tables and , respectively. The metal-centered Pt–N (2.033 and 2.027 Å) and Pt–O (2.020 and 2.024 Å) bond lengths are similar and comparable to the few literature examples of N-donor Pt­(CBDCA) (CBDCA = 1,1-cyclobutanedicarboxylic acid) complexes. − In 4 , the chelate amino groups form intramolecular hydrogen bonds with the N atoms of the NMe 2 groups, N15···N23 [ d (D···A) = 2.925(5) Å], as seen in complexes 2 and 3 .…”

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

“…The formation of 2b suggests that the 3,7-dicarboxylate substituents stabilize the 9,9-diol function by removal of electron density from the N atoms, similar to protonation and metal coordination. Interestingly, the 9,9-diol stabilization is not effected by 1,5-dicarboxylate substitution at the bispidin-9-one C atoms, as will be described elsewhere in detail…”

“…It is quite soluble in DMSO and DMF. According to X-ray analysis, D2 is isomorphous to the parent (C 7 H 14 N 2 )­Pt­{C 4 H 6 (CO 2 ) 2 }­·5H 2 O ( A2 ) and also the 9-oxabispidine derivative (OC 6 H 12 N 2 )­Pt­{C 4 H 6 (CO 2 ) 2 }­·5H 2 O ( C2 ) (in contrast to the 9,9-diol {(HO) 2 C 7 H 12 N 2 }­Pt­{C 4 H 6 (CO 2 ) 2 }­·2H 2 O ( B2 ) which forms a dihydrate) …”

“…2)) is isomorphous to the structures of (C 7 H 14 N 2 )­Pt­{C 4 H 6 (CO 2 ) 2 }­·5H 2 O ( A2 ) and (OC 6 H 12 N 2 )­Pt­{C 4 H 6 (CO 2 ) 2 }­·5H 2 O ( C2 ), whereas the 9,9-diol derivative crystallizes with a lower defined water content, {(HO) 2 C 7 H 12 N 2 }­Pt­{C 4 H 6 (CO 2 ) 2 }­·2H 2 O ( B2 ; space group P 4/ n (No. 85)) . There are 2 independent Pt complexes and 10 water molecules in the asymmetric unit of D2 .…”

Optimization of Hexadentate Bispidine Ligands as Chelators for 64CuII PET Imaging

“…Among the range of well‐established ligands used in this field, due to the facile synthesis, the large synthetic variability, the ease of derivatization with biological vectors and the relatively high complex stability and inertness, bispidines (3,7‐diazabicyclo[3.3.1]nonanes; see Figure for the bispidine ligands discussed in this manuscript) have been shown to have significant advantages for 64 Cu‐based PET imaging . Among other reasons, these arise from the rigid adamantane‐derived backbone—preorganized and complementary for tetragonally distorted octahedral geometries—that is well suited and selective for binding Cu II ; it is also for this reason that bispidines have been described as a favorable ligand platform for medicinal applications . In addition to radiopharmaceutical chemistry, applications of Cu–bispidines include aziridination catalysis, and hemocyanine and catecholase biomimetic chemistry …”