Synthesis, cytotoxicity and cucurbituril binding of triamine linked dinuclear platinum complexes.
The platinum complexes trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3NH2(CH2)3NH2)]3+ (CT033) and the corresponding N4-dimethyl linked analogue trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3N(Me)2(CH2)3NH2)]3+ (CT233) have been synthesised, and their cytotoxicity, ability to bind cucurbit[7,8]uril (Q[7,8]) and reaction with cysteine studied. Both platinum complexes show good activity in the L1210 cell line and maintain their activity in the corresponding cisplatin L1210/DDP cell line. However, the N4-dimethyl analogue CT233 is approximately 50-times less active than the CT033 complex. This suggests that the insertion of a positive charge into the linking ligand may not, per se, be responsible for the higher cytotoxicity generally observed for dinuclear platinum complexes linked by polyamines. The upfield shifts of the resonances from the methylene protons in the linking triamine ligand observed in the 1H NMR spectra of either CT033 and CT233 upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand. However, the results show that the protonated secondary amine in CT033 acts as a barrier to encapsulation, with the Q[7,8] being positioned over only one propyl-arm at a time. Alternatively, the entire triamine linking ligand of CT233 is fully encapsulated within the Q[7,8] cavity. Encapsulation by Q[7,8] was found to reduce the rate of reaction of CT033 and CT233 with the thiol containing amino acid cysteine, with a greater rate reduction observed for CT233. These results are consistent with the NMR results of the Q[7,8] binding studies of the two platinum complexes. For CT033 encapsulated in Q[7,8], one of the two platinum centres is completely exposed to the solvent, whereas, for CT233 both platinum centres are simultaneously positioned within the portals of the cucurbit[n]uril, thereby, affording greater protection.
Zhao
Yunjie
Y
School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australian Defence Force Academy, Northcott Drive, Campbell, ACT 2600, Australia.
Bali
Mark S
MS
Cullinane
Carleen
C
Day
Anthony I
AI
Collins
J Grant
JG
D000588:Amines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047028:Macrocyclic Compounds / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000099246:Cucurbit(n)urils
D000588:Amines; D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D009944:Organoplatinum Compounds; D000099246:Cucurbit(n)urils