Iridium(III)-Based Infrared Two-Photon Photosensitizers: Systematic Regulation of Their Photodynamic Therapy Efficacy.

Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing YQ2 was found to be the most potent infrared two-photon excitable photosensitizer in a 4 × 3 combination library of cyclometalated Ir(III) complexes. YQ2 could enter cells via an energy-dependent and caveolae-mediated pathway, bind specifically to mitochondria, produce 1O2 in response to 808 nm LPL irradiation, activate caspases, and induce apoptosis. In vitro, YQ2 displayed a remarkable phototherapy index for both malignant melanoma (>885) and non-small-cell lung cancer (>1234) based on these functions and was minimally deleterious to human normal liver and kidney cells. In in vivo antitumor phototherapy, YQ2 inhibited tumor growth by an impressive 85% and could be eliminated from the bodies of mice with a half-life as short as 43 h. This study has the potential to contribute significantly to the development of phototherapeutic drugs that are extremely effective in treating large, profoundly located solid tumors as well as the understanding of the structure-activity relationship of Ir(III)-based PSs in PDT.

Scorpion-Shaped Zinc Porphyrins as Tetrafunctional TAR RNA Predators and HIV-1 Reverse Transcriptase Inhibitors.

HIV-1 reverse transcriptase (RT) inhibitors are fundamental to the discovery and development of anti-HIV drugs. Their main target is RT, and only a tiny number of them can bind to viral RNA. In this paper, five new Zn(II) porphyrin compounds were developed with different characters. ZnTPP4 has both the appearance and the functions of a scorpion with a rigid tail and stinger to selectively hunt HIV-1 TAR RNA based on the molecular recognition of hydrogen bonds, a fierce chelicera to bite RNA by metal coordination, mighty pedipalps to grasp the bound RNA by supramolecular inclusion, and a broad body maintaining the configuration of each functional area so that they can cooperate with each other and providing accommodation space for the bound RNA. This tetrafunctional Zn(II) porphyrin is relatively nontoxic to normal cells and can produce sensitive responses for RNA. Moreover, this work offers practical construction methodologies for medication of AIDS and other diseases closely related to RT like EBOV and SARS-CoV-2.

Cyclometalated Iridium(III) Complexes as High-Sensitivity Two-Photon Excited Mitochondria Dyes and Near-Infrared Photodynamic Therapy Agents.

Photodynamic therapy (PDT) using two-photon near-infrared light excitation is a very effective way to avoid the use of short-wavelength ultraviolet or visible light which cannot efficiently penetrate into the biological tissues and is harmful to the healthy cells. Herein, a series of cyclometalated Ir(III) complexes with a structurally simple diimine ligand were designed and the synthetic route and preparation procedure were optimized, so that the complexes could be obtained in apparently higher yield, productivity, and efficiency in comparison to the traditional methods. Their ground state and excited singlet and triplet state properties were studied by spectroscopy and quantum chemistry theoretical calculations to investigate the effect of substituent groups on the photophysical properties of the complexes. The Ir(III) complexes, especially Ir1 and Ir3, showed very low dark toxicities and high phototoxicities under both one-photon and two-photon excitation, indicating their great potential as PDT agents. They were also found to be highly sensitive two-photon mitochondria dyes.

Polypyridyl ruthenium complexes as bifunctional TAR RNA binders and HIV-1 reverse transcriptase inhibitors.

Inhibitors of type 1 human immunodeficiency virus (HIV-1) reverse transcriptase are central to anti-HIV therapy. Most of their targets are enzymes, while very few could bind to viral RNA. Here we designed four new polypyridyl Ru(II) complexes, which could bind HIV-1 TAR RNA tightly and selectively by molecular recognition of hydrogen bonds, further stabilize the Ru(II)-RNA bound system by electrostatic attraction, and efficiently inhibit the Moloney murine leukemia virus (M-MuLV) and HIV-1 reverse transcriptase. The polypyridyl Ru(II) complexes also have physical and chemical advantages, including high chemical stability and photostability, sensitive spectroscopic responses to HIV TAR RNA, and low toxicity to normal cells. This work also provides valuable drug design strategies for acquired immune deficiency syndrome (AIDS) and other reverse transcriptase related disease research, such as hepatitis C virus (HCV), Ebola virus (EBOV), influenza A virus, and most recently the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Novel polypyridyl ruthenium complexes acting as high affinity DNA intercalators, potent transcription inhibitors and antitumor reagents.

Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model compound [Ru(bpy)2(pip)]2+ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline). As shown in the optimized geometry of the complexes, the introduction of styryl group not only extended the conjugated area of the intercalative ligand, but also retained the excellent planarity. These two merits have been proven to be beneficial for their DNA intercalation, thus greatly improved their inhibition activity towards DNA transcription by RNA polymerase and DNA topoisomerase, two enzymes closely related to both DNA and tumor cell growth. The relationships between the substituent group structures and the biological activities have also been investigated from energetic and electronic aspects by quantum chemistry calculations. Results from cell cytotoxicity and apoptosis assay testified that the styryl substituted ruthenium complexes possessed higher antitumor activity than [Ru(bpy)2(pip)]2+, as expected. As quantified in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the tumor cell death is caused mostly through apoptosis for Ru2 and Ru3, while non-apoptotic processes for Ru1, Ru4 and Ru5. In vitro fluorescence evaluation revealed that all complexes located mainly in cytoplasm, but the three complexes with high antiproliferative activity could enter nucleus. All complexes have shown apparent lower cytotoxicity towards normal human colon epithelial cell CCD-841-CON than the examined tumor cell lines.