A comparison of DNA binding profiles of dinuclear platinum compounds with polyamine linkers and the trinuclear platinum phase II clinical agent BBR3464

Abstract

The DNA binding profiles of three bis Pt(II) polyamine-linked compounds, [[ trans-PtCl(NH(3))(2)](2)[mu-spermine- N(1), N(12)]](4+), [[ trans-PtCl(NH(3))(2)](2)[mu-spermidine- N(1), N(8)]](3+), and [[ trans-PtCl(NH(3))(2)](2)[mu-BOC-spermidine]](2+), were compared with that of a novel trinuclear phase II clinical agent, [[ trans-PtCl(NH(3))(2)](2)[mu- trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2)]](4+). All of the compounds bind preferentially in a bifunctional manner, according to unwinding of supercoiled DNA circles. The kinetics of binding of these compounds corresponds to their relative charge (2+ to 4+). The preference for the formation of interstrand crosslinks, however, does not follow a charge-based pattern. By studying the results of DNA polymerase extension products on a DNA template modified by the compounds, and by incorporating the complementary method of RNA transcription mapping, it was possible to determine the nucleotide bases that are preferred sites of binding. The stop sites due to platinum adducts were determined, and some preliminary observations concerning the range and type of crosslinks were established. It can be concluded that dinuclear Pt compounds are similar to their trinuclear counterpart, and that charge differences do not contribute solely to the variances between the compounds.

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

“…The effect of the degree of flexibility of the compounds tested as anticancer drugs is clearly reflected in the results presently obtained for compound III (IC 50 value toward HeLa cells equal to 5 µM (Table 1)) when compared to the ones reported for the cationic trinuclear Pt(II) chelate BBR3464 (a bifunctional (1,0,1/ttt) type complex of formula [Pt(NH 3 ) 2 ] 3 -[H 2 N(CH 2 ) 6 NH 2 ] 2 Cl 2 ), which displays a higher (and equally irreversible) cytotoxic potency in similar types of cancer cells (e.g., 0.012 µM against the A2780 ovarian carcinoma line). 16,17,19,29,30 …”

“…The presence of more than one metal center in these Pt(II) multifunctional chelates is thus expected to lead to a higher efficacy and specificity regarding DNA binding (e.g., increased number of interstrand crosslinks, 28 possibly at more than one position). In addition, each type of polynuclear platinum structure (e.g., number and nature of the leaving groups and their geometry relative to the bridging amines) has been shown, in recent studies, to have its own particular cytotoxic characteristics (e.g., triplatinum BBR3464, currently in phase III of clinical trials 16,17,19,29,30 ). In fact, it is known that a simple chemical modification in the structure of a certain compound may alter its DNA binding properties and/or the relative amounts of interstrand crosslinks in double-stranded DNA, thus governing its antiproliferative and cytotoxic activity.…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…161 Whilst BBR3464 displays higher and faster uptake into cisplatin sensitive and resistant cells, 162,163 and faster DNA binding with more DNA adducts formed compared with cisplatin, [164][165][166] it is the formation of a range of unique DNA adducts that are thought to be the mechanism by which it derives its potent cytotoxicity. Whereas cisplatin forms rigid, short-range intrastrand adducts, the adducts of BBR3464 are more commonly defined as flexible and long range, with a high degree of interstrand cross-links.…”

Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

“…3) [29]. Free cisplatin is known to react with guanosine/DNA in a relatively short time period (t 1/2 = 0.5-4 h) [29][30]. For our drug-dendrimer complexes the platinum release is significantly slower and in fact never goes to theoretical completion (see Table 1 [18], and these are likely to also be formed by our aquated cisplatin.…”