Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates

Abstract

We report the cytotoxicity toward B16 cells and antitumor activity in three transplantable tumor models of a series of ionic, tetrahedral, bischelated gold diphosphine complexes of the type [Au1(R2PYPR2')2]X, where Y = (CH2)2, (CH2)3, or cis-CH = CH. The anion (X = Cl, Br, I, CH3SO3, NO3, PF6) had little effect upon activity. The R = R' = phenyl complexes 1, 7, and 8 [Y = (CH2)2, (CH2)3, cis-CH = CH, X = Cl] were the most active against P388 leukemia, with an increase in lifespan ranging from 83 to 92% and were also active against M5076 sarcoma and B16 melanoma. Complexes with pyridyl or fluorophenyl substituents had reduced activities. For the latter, 19F and 31P NMR were used to verify the formation of bischelated gold(I) complexes in solution. The reduced activity of the complex with R = Et and R' = Ph and inactivity with R = R' = Et are discussed in terms of their increased reactivity as reducing agents. 31P NMR studies show that [AuI(Et2P(CH2)2PPh2)2]Cl readily reacts with serum, albumin, and Cu2+ ions to give oxidized ligand.

Targeting the mitochondrial cell death pathway with gold compounds

“…[Au(dppe) 2 ] + was selected for pre-clinical trials, but was abandoned when severe hepatotoxicity was observed in dogs. Structure activity relationships were evaluated for a wide range of diphosphine ligands and their metal complexes [2,75]. For complexes of the type [Au(R 2 P(CH 2 ) n PR 2 ) 2 ]X highest activity was found where R = R = phenyl and n = 2, 3 or cis-CH CH.…”

Role of chelates in treatment of cancer

“…The anion (X = Cl, Br, I, CH 3 SO 3 , NO 3 , PF 6 ) had little effect upon activity. [32] 2. Antitumor agents gold-monophosphine and golddiphosphine derivatives show activity against nonsmall lung, colon, CNS, renal, prostate, breast and ovarian cancer.…”

Non-Platinum Antitumor Compounds

“…In addition, significant activity was demonstrated in the 11210 leukaemia, the M5076 reticulum cell carcinoma, the B16 melanoma, the mammary adenocarcinoma 16/c (all of these are intraperitoneally transplanted and intraperitoneally treated), and the ADJ/PC6 blastocytoma (subcutaneously transplanted). [Au(dppeh]CI (Fig.12c) [210] is also active, showing comparable activity in the P388 leukaemia, but showed no activity when administered intravenously or subcutaneously. Activity can only be achieved by local application to the tumor.…”