👤 Masako Uemura

We investigated the cationic dinuclear Pt(II) complex AMPZ ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-pyrazolato)](NO₃)₂) as a tool for constructing biological metal-organic frameworks (bio-MOFs) via liquid-liquid phase separation (LLPS). AMPZ efficiently induced LLPS in 44- or 45-mer single-stranded DNA (ssDNA) fragments, generating droplets whose properties depended on the relative abundance of nucleobase and the presence or absence of coordination interactions with AMPZ. In guanine-rich ssDNA, AMPZ promoted droplet gelation through cross-linking and formation of a coordination-bonded network, whereas adenine-rich, guanine-deficient ssDNA did not undergo gelation. ¹H nuclear magnetic resonance analysis of reactions between AMPZ and mononucleosides or mononucleotides revealed that nucleobase-dependent differences in droplet properties arise from distinct reaction mechanisms and kinetics. Notably, AMPZ and adenine form a unique 1:1 complex in which the N7 nitrogen and deprotonated N6-NH of adenine coordinate to the two Pt(II) ions of AMPZ, forming an eight-membered chelate. This chelate prevents cross-linking of adenine-rich ssDNA and the subsequent gel transition. AMPZ and cytosine also provide a similar 1:1 chelate complex. These findings demonstrate that AMPZ modulates droplet formation and properties in a nucleobase-dependent manner. The mechanistic insights uncovered here provide a new strategy for constructing bio-MOFs via LLPS, exploiting the two-step interactions between AMPZ and DNA. Show less

Coacervates are dense aqueous phases that form by liquid-liquid phase separation. Seven Pt(II) complexes with different charges and nucleotide reactivities were examined for their ability to induce coacervate formation in a 21-mer single-stranded DNA (ssDNA). Only AMPZ ([cis-{Pt(NH₃)₂}₂(μ-pyrazolato)(μ-OH)](NO₃)₂), a cationic dinuclear Pt(II) complex, efficiently induced coacervate formation in ssDNA containing only thymine (T21-DNA). AMPZ has very low reactivity with thymine but relatively high reactivity with guanine, and when three of the thymines in T21-DNA were substituted with a guanine to produce T18-G3-DNA, the resulting coacervate was observed to undergo gelation via the formation of an extensive Pt-DNA coordination-bonded network. We then examined the construction of coacervates that comprise multiple phases by adding AMPZ to a mixture of two types of ssDNAs, a highly reactive T10-G11-DNA and a minimally reactive T21-DNA, and found that two distinct assembly states─a cell mimetic assembly and a DNA-encapsulating gel─could be formed. Show less

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-azolato)]X₂, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling. Therefore, here we investigated the potential of 14 such complexes as agents for the treatment of prostate cancer by examining their antiproliferative activity in the human prostate adenocarcinoma cell line LNCaP. Several of the complexes, particularly 5-H-Y ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-tetrazolato-N2,N3)](ClO₄)₂), effectively inhibited LNCaP cell growth, even at low concentrations, by direct modulation of AR signaling, and by binding to DNA and inducing apoptosis, which is a common mechanism of action of Pt-based drugs such as cisplatin (cis-diamminedichloridoplatinum(II)). Comparative analysis with cisplatin revealed superior inhibitory effects of these complexes. Further investigation revealed that 5-H-Y suppressed mRNA expression of genes downstream from AR and induced apoptosis, particularly in cells overexpressing AR, highlighting its potential as an AR antagonist. Thus, we provide here insights into the mechanisms underlying the antiproliferative effects of azolato-bridged complexes in prostate cancer. Show less

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-R-tetrazolato-N2,N3)]²⁺; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo. Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH₂, CF₂H, or CF₃), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-difluoromethyltetrazolato-N2,N3)](NO₃)₂, showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities. Show less