👤 Huang SY

Investigating the role of lysosome dysfunction in cancer requires the development of efficient probes for lysosomes. We report herein a cyclometalated iridium(iii) complex (Ir-Ly) as a luminescent probe for visualizing lysosomes in cancer cells. The morpholine and hydroxy moieties within Ir-Ly provide suitable hydrophilicity and responsiveness to pH. Importantly, Ir-Ly exhibits a large Stokes shift, long lifetime and high photostability, which are important advantages for lysosome tracking in living cells. Show less

Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(iii) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(iii) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases. Show less

Protein inactivation by reactive oxygen species (ROS) such as singlet oxygen ((1)O2) and superoxide radical (O2(•-)) is considered to trigger cell death pathways associated with protein dysfunction; however, the detailed mechanisms and direct involvement in photodynamic therapy (PDT) have not been revealed. Herein, we report Ir(III) complexes designed for ROS generation through a rational strategy to investigate protein modifications by ROS. The Ir(III) complexes are effective as PDT agents at low concentrations with low-energy irradiation (≤ 1 J cm(-2)) because of the relatively high (1)O2 quantum yield (> 0.78), even with two-photon activation. Furthermore, two types of protein modifications (protein oxidation and photo-cross-linking) involved in PDT were characterized by mass spectrometry. These modifications were generated primarily in the endoplasmic reticulum and mitochondria, producing a significant effect for cancer cell death. Consequently, we present a plausible biologically applicable PDT modality that utilizes rationally designed photoactivatable Ir(III) complexes. Show less

A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate β-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that β-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation. Show less

The synthesis and characterization of ruthenium compounds (Ru1-Ru12) of the type [Ru(S)(2)(K)], (where S=1,10-phenanthroline/2,2'-bipyridine and K=itsz, MeO-btsz, 4-Cl-btsz, 2-Cl-btsz, 2-F-btsz, hfc and itsz=isatin-3-thiosemicarbazone, MeO-btsz=1-(4'-methoxy-benzyl)-thiosemicarbazone, hfc=2-{[3-chloro-4-fluoro-phenylimino]methyl}phenol, 4-Cl-btsz=1-(4'-chlorobenzyl)-thiosemicarbazone, 2-Cl-btsz=1-(2'-chloro benzyl)-thiosemicarbazone, 2-F-btsz=1-(2'-fluorobenzyl)-thiosemicarbazone) are described. These ligands form bidentate octahedral ruthenium compounds. The title compounds were subjected to in vivo anticancer activity against a transplantable murine tumor cell line Ehrlich's Ascites Carcinoma (EAC) and in vitro cytotoxic activity against human cancer cell line Molt 4/C8, CEM and murine tumor cell line L1210. Ruthenium compounds (Ru1-Ru12) showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these compounds prolonged the life span of mice bearing EAC tumor by 10-43%. In vitro evaluation of these ruthenium compounds revealed cytotoxic activity from 0.24 to 27 microM against Molt 4/C8, 0.27 to 48 microM against CEM, and 0.94 to 248 microM against L1210. Their ligands alone failed to show cytotoxic activity at the concentrations tested (68-405 microM). Show less