Os₂–Os₄ Switch Controls DNA Knotting and Anticancer Activity

Abstract

Dinuclear trihydroxido-bridged osmium-arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged Os II -arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity.Platinum drugs are used in over 50 % of all chemotherapeutic regimens.[1] The basis for their activity is believed to be mainly due to DNA binding, in particular to changes in DNA conformation. [2] Resistance to Pt drugs is a clinical drawback that might be overcome by designing new drugs that induce distinctly different conformational changes in DNA.[3] Multinuclear metal complexes provide a promising strategy for such an approach. [4] Herein, we consider the design of multinuclear "pianostool" organo-osmium complexes. Half-sandwich Os II arene complexes exhibit antitumor activity both in vitro and in vivo.[ Tables S1, S2.Very few X-ray structures of hydroxido-bridged osmium-(II) arene complexes have been reported since the early study Figure S1. The distance between the Os atoms bridged by pap is 13.175 (1), and almost half (6.995 ) with the prz bridge (2). DFToptimized geometries are in good agreement with these structures (Tables S3-S5). UV/Vis absorption spectra were recorded for 1 and 2 in acetone ( Figure S2). Time-dependent Density Functional Theory (TDDFT) singlet excited state calculations for both complexes showed that the absorption band at 435-450 nm has 1 MLCT (metal-to-ligand chargetransfer) character and is composed of two major transitions involving Os-based occupied orbitals and ligand-based LUMO and LUMO + 1 ( Figure S2). Notably, MLCT transitions at wavelengths higher than 600 nm are found for 1, in agreement with the experimental spectrum. The intensity of such TDDFT transitions is overestimated (particularly the singlet electronic transition S3), as expected for highly delocalized systems displaying charge-transfer bands.[9]The stability of the tetramer 1 in solution was investigated first in [D 6 ]acetone. The 1 H NMR spectra of 1· [PF 6 ] 4 at 298 K showed two singlets at 6.68 and 6.66 ppm assignable as OH peaks ( Figure S3A). This appears to be the first detection of peaks for bridging-OH groups in organometallic tetranuclear complexes.[10] To confirm this assignment, 1 H NMR at various temperatures and 2D 1 H DOSY NMR spectra were recorded. The two OH singlets shifted downfield reversibly at lower temperature ( Figure S3 and S4) with a linear temperature dependence (Dd/DT = À0.009 ppm K À1 ). Interestingly, two peaks assignable to H 2 O and HOD were also observed in these [D 6 ]acetone solutions ( Figure S5).[11] When H 2 O (10 mL) was added, the H 2 O and OH bridge peaks shifted downfield ( Figure S6). The two low-fi...

Biomedically Relevant Self-Assembled Metallacycles and Metallacages

“…91 An important part of MOCs' biological applications is how to confirm the precise mode of interaction between MOCbased anticancer drugs with DNA. 92 Very recently, Yang prepared MOCs for selective therapy of cancers with controllable 1 O 2 release. 93 Furthermore, enzyme-mimetic metallacages offers the possibility of MOC-related bionics applications.…”