A positively charged trinuclear 3N-chelated monofunctional platinum complex with high DNA affinity and potent cytotoxicity

Abstract

A trinuclear 3N-chelated monofunctional platinum complex, [Pt3(HPTAB)Cl3](ClO4)3 (HPTAB = N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene), has been structurally characterized, which binds to DNA and demonstrates much higher potency against the murine leukemia cell line (P-388) and the human nonsmall-cell lung cancer cell line (A-549) than cisplatin.

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

“…The intrametal distance in 2 is 8.099 ( Figure S1 in the Supporting Information), which is comparable to those found in 1 (6.986, 7.267, and 8.359 ), as reported previously. [15] These distances appear to match well with that of two N7 positions of purine (Pu) residues (ca. 8.3 ) within PuXPu sequences in B-DNA.…”

“…Under the same experimental conditions, cisplatin displayed a similar tendency for the two DNA forms but a coalescence point was not observed even at r i = 0.36. [15] The result indicates that both complexes 1 and 2 exert more perturbation on the tertiary structure of negatively supercoiled DNA than cisplatin, and complex 1 is six times more potent than complex 2. Moreover, the circular dichroism (CD) spectra of calf-thymus DNA (CT-DNA) platinated by 1 displayed a more significant elliptical decrease in the negative band [15] than that of 2 ( Figure S3 in the Supporting Information), which again implies the distinctive efficacy of 1 in unwinding the DNA helix and deviating DNA conformation from B-DNA.…”

“…The coalescence point r i (c), at which the supercoiled and relaxed forms comigrate, [18] was 0.06 for complex 1 [15] and 0.36 for complex 2 ( Figure S2 in the Supporting Information). Under the same experimental conditions, cisplatin displayed a similar tendency for the two DNA forms but a coalescence point was not observed even at r i = 0.36.…”

“…[11][12][13] In the search for more stable polynuclear Pt II complexes, we have designed several di-and trinuclear complexes in which the Pt II centers are bridged by bulky aromatic linkers. [14][15][16] These complexes showed interesting cytotoxicity against human and mouse cell lines. Amongst them, a trinuclear platinum complex (1) bridged by N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene (hptab) exhibits significantly higher cytotoxicity than cisplatin and is stable in the presence of excess GSH.…”

“…Amongst them, a trinuclear platinum complex (1) bridged by N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene (hptab) exhibits significantly higher cytotoxicity than cisplatin and is stable in the presence of excess GSH. [15] Given such promise, it would be interesting to carry out comprehensive studies to reveal structural and chemical factors that potentially govern the activity of complex 1. Toward this goal, we herein report the preparation and structural characterization of its dinuclear analogue (2), and the investigation of its cytotoxicity against the same tumor cell lines.…”