Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure

In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003 , 1718; Coord. Chem. Rev. 2009 , 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso‐aryl rings were prepared, and these complexes were used to study the structure–bioactivity relationship. The cytotoxic IC₅₀ values of [Au(Por)]⁺ (Por=porphyrinato ligand), which range from 0.033 to >100 μM , correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)–porphyrin with saccharide conjugation [Au(4‐glucosyl‐TPP)]Cl ( 2 a ; H₂(4‐glucosyl‐TPP)=meso‐tetrakis(4‐β‐D ‐glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC₅₀=1.2–9.0 μM ) without causing cell death and is much less toxic to lung fibroblast cells (IC₅₀>100 μM ). The gold(III)–porphyrin complexes induce S‐phase cell‐cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)–porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9×10⁵ to 4.1×10⁶ dm³ mol^?1 as determined by absorption titration. Complexes 2 a and [Au(TMPyP)]Cl₅ ( 4 a ; [H₂TMPyP]⁴⁺=meso‐tetrakis(N‐methylpyridinium‐4‐yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4 a , a gold(III) derivative of the known G‐quadruplex‐interactive porphyrin [H₂TMPyP]⁴⁺, can similarly inhibit the amplification of a DNA substrate containing G‐quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2 a and the parental gold(III)–porphyrin 1 a do not display a significant inhibitory effect (<10 %) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti‐apoptotic bcl‐2 protein is a potential target for those gold(III)–porphyrin complexes with apoptosis‐inducing properties. Complex 2 a also displays prominent anti‐angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti‐angiogenic activities.     

Factors Affecting DNA–DNA Interstrand Cross‐Links in the Antiparallel 3′–3′ Sense: A Comparison with the 5′–5′ Directional Isomer

Reported herein is a study of the unusual 3′–3′ 1,4‐GG interstrand cross‐link (IXL) formation in duplex DNA by a series of polynuclear platinum anticancer complexes. To examine the effect of possible preassociation through charge and hydrogen‐bonding effects the closely related compounds [{trans‐PtCl(NH₃)₂}₂(μ‐trans‐Pt(NH₃)₂{NH₂(CH₂)₆NH₂}₂)]⁴⁺ (BBR3464, 1 ), [{trans‐PtCl(NH₃)₂}₂(μ‐NH₂(CH₂)₆NH₂)]²⁺ (BBR3005, 2 ), [{trans‐PtCl(NH₃)₂}₂(μ‐H₂N(CH₂)₃NH₂(CH₂)₄)]³⁺ (BBR3571, 3 ) and [{trans‐PtCl(NH₃)₂}₂{μ‐H₂N(CH₂)₃‐N(COCF₃)(CH₂)₄}]²⁺ (BBR3571‐COCF₃, 4 ) were studied. Two different molecular biology approaches were used to investigate the effect of DNA template upon IXL formation in synthetic 20‐base‐pair duplexes. In the “hybridisation directed” method the monofunctionally adducted top strands were hybridised with their complementary 5′‐end labelled strands; after 24 h the efficiency of interstrand cross‐linking in the 5′–5′ direction was slightly higher than in the 3′–3′ direction. The second method involved “postsynthetic modification” of the intact duplex; significantly less cross‐linking was observed, but again a slight preference for the 5′–5′ duplex was present. 2D [¹H, ¹⁵N] HSQC NMR spectroscopy studies of the reaction of [¹⁵N]‐ 1 with the sequence 5′‐d{TATACATGTATA}₂ allowed direct comparison of the stepwise formation of the 3′–3′ IXL with the previously studied 5′–5′ IXL on the analogous sequence 5′‐d(ATATGTACATAT)₂. Whereas the preassociation and aquation steps were similar, differences were evident at the monofunctional binding step. The reaction did not yield a single distinct 3′–3′ 1,4‐GG IXL, but numerous cross‐linked adducts formed. Similar results were found for the reaction with the dinuclear [¹⁵N]‐ 2 . Molecular dynamics simulations for the 3′–3′ IXLs formed by both 1 and 2 showed a highly distorted structure with evident fraying of the end base pairs and considerable widening of the minor groove.