A hypoxia-activated NO donor for the treatment of myocardial hypoxia injury.

As present NO donor drugs cannot localize to release NO at the hypoxic site, along with the short half-life and bidirectional regulation of NO, they are unable to overcome low bioavailability and side effects in the treatment of myocardial hypoxia injury. In this study, we designed and prepared a novel hypoxia-activated NO donor (Hano) by hybridization of a known NO donor compound (Nno) with a hypoxia-activated group. Hano and isosorbide dinitrate were compared in terms of NO release and anti-myocardial hypoxia injury. Furthermore, the effects of Hano and Nno on releasing NO, dilating blood vessels, and preventing myocardial hypoxia injury were studied and compared in smooth muscle cells, cardiomyocytes and mice. The results showed that the NO release by Hano increased either in smooth muscle cells or in myocardial cells under hypoxia conditions. Significantly, Hano was found capable of dilating blood vessels and attenuating hypoxia injury both in vitro and in vivo, and has great potential as a hypoxia-activated NO donor drug to treat hypoxic heart diseases.

Multifunctional platinum(IV) complex bearing HDAC inhibitor and biotin moiety exhibits prominent cytotoxicity and tumor-targeting ability.

Despite the wide clinical use of platinum drugs in cancer treatment, their severe side effects and lack of tumor selectivity seriously limit their further clinical application. To address the limitations of the current platinum drugs, herein a multifunctional platinum(IV) compound 1 containing a histone deacetylase (HDAC) inhibitor (4-phenylbutyric acid, 4-PBA) and a tumor-targeting group (biotin) has been designed and prepared. An in vitro cytotoxicity study indicated that compound 1 exhibits comparable or superior cytotoxicity to cisplatin against the tested cancer cell lines, but greatly reduced toxicity in human normal liver LO2 cells, implying the potential tumor-targeting ability of compound 1. Molecular docking results indicate that compound 1 can effectively interact with a biotin-specific receptor (streptavidin) through its biotin moiety, enabling potential tumor-targeting capability. Further studies indicated that compound 1's cytotoxicity stems from inducing DNA damage via the mitochondrial apoptotic pathway and inhibiting HDACs. Consequently, this compound can not only take advantage of the tumor selectively of biotin to improve its tumor-targeting ability but also strengthen its anticancer activity via simultaneously targeting DNA and HDACs.

Discovery of 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol Derivatives as Glutathione Transferase Inhibitors with Favorable Selectivity and Tolerated Toxicity.

Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.

DNA-Targeting RuII -Polypyridyl Complex with a Long-Lived Intraligand Excited State as a Potential Photodynamic Therapy Agent.

Subtle ligand modifications on RuII -polypyridyl complexes may result in different excited-state characteristics, which provides the opportunity to tune their photo-physicochemical properties and subsequently change their biological functions. Here, a DNA-targeting RuII -polypyridyl complex (named Ru1) with highly photosensitizing 3 IL (intraligand) excited state was designed based on a classical DNA-intercalator [Ru(bpy)2 (dppz)]⋅2 PF6 by incorporation of the dppz (dipyrido[3,2-a:2',3'-c]phenazine) ligand tethered with a pyrenyl group, which has four orders of magnitude higher potency than the model complex [Ru(bpy)2 (dppz)]⋅2 PF6 upon light irradiation. This study provides a facile strategy for the design of organelle-targeting RuII -polypyridyl complexes with dramatically improved photobiological activity.

A naphthalimide derivative can release COS and form H2S in a light-controlled manner and protect cells against ROS with real-time monitoring ability.

As an important gasotransmitter, hydrogen sulfide having multiple biological roles cannot be easily probed in cells. In this study, a light controllable H2S donor, Nap-Sul-ONB, derived from naphthalimide was developed. Under the irradiation of 365 nm light, a readily controlled stimulus, the donor could release COS to form H2S and exhibit turn on fluorescence to indicate the release of payload and its cellular location. Besides, the ROS scavenging ability and cell protective effect of Nap-Sul-ONB against endogenous and exogenous ROS were studied. The results showed that upon 365 nm light irradiation, Nap-Sul-ONB could reduce the cellular ROS level and increase the survival rate of PMA-treated cells.

A lysosome specific theranostic NO donor inhibits cancer cells by stimuli responsive molecular self-decomposition with an on-demand fluorescence pattern.

The anticancer mechanism of NO is difficult to study owing to its short lifetime and high reactivity. Thus, a theranostic anticancer NO donor assembled with NO on-demand release abilities, accurate lysosome location capabilities and signal feedback behavior was developed. Profiting from the theranostic properties, the specific mechanism was comprehensively studied. Spectral and cell imaging studies revealed that the as prepared NO donors could release NO in solution or within cancer cells. Fluorescence co-dyeing experiments demonstrated that Mo-Nap-NO entered lysosomes specifically and disrupted them after being triggered by light. Upon irradiation with 460 nm visible light, both the donors demonstrated considerable in vitro anticancer effects. A further mechanistic study showed that after entering the lysosome and being triggered by 460 nm irradiation, NO ruptured the lysosome, resulting in the release of cathepsin D into the cytosol, which activated the caspase3 mediated apoptosis pathway.

Combination of 7-hydroxycoumarin in a platinum(IV) complex derived from cisplatin enhanced cytotoxicity with multiple mechanisms of action.

A novel compound, Cou-platin, composed of 7-hydroxycoumarin and a platinum(IV) moiety derived from cisplatin was designed and synthesized. Significantly, Cou-platin exhibited more potent in vitro antitumor activity against all tested cancer cell lines than that of cisplatin, which was mainly attributed to the liberation of cisplatin and 7-hydroxycoumarin upon reduction with a biomolecular agent. Besides, cellular accumulation of Cou-platin was dramatically increased among several cancer cells in contrast to cisplatin. Flow cytometry study revealed that Cou-platin arrested cell cycle at G2 phase and induced cell apoptosis. Western blots results indicated that it not only activated cell apoptosis pathway, but also inhibited extracellular regulated protein kinases/mitogen-activated protein kinase pathway. In vivo tests showed that Cou-platin, at equimolar dose to cisplatin, could inhibit tumor growth in nude mouse HCT116 tumor xenograft models almost as cisplatin and oxaliplatin, but with less toxicity.

A study on platinum(iv) species containing an estrogen receptor modulator to reverse tamoxifen resistance of breast cancer.

Several dual-action Tam-Pt(iv) complexes derived from tamoxifen (Tam) and platinum(ii) drugs were designed and synthesized for targeting estrogen receptors (ERs) and DNA. These novel compounds not only exhibited potent cytotoxicity against breast cancer cells, but also reversed the tamoxifen resistance of TamR-MCF-7 cancer cells. Computational docking assays together with cellular uptake data demonstrated that the ER ligand portion of these conjugates plays a targeting role in ER-positive tumor cells and promotes the uptake of platinum via an estrogen receptor-mediated pathway. A study on the preliminary mechanism of the typical conjugate, complex 1, revealed that the Tam-Pt(iv) complex induced apoptosis via the mitochondrial-dependent apoptosis pathway mediated through the activation of caspase 3 and PARP proteins. These results suggested that the conjugation of estrogen receptor modulators with the platinum moiety could facilitate a selective enrichment of platinum in estrogen-positive tumors and possibly broaden the scope of ER ligand clinical use to resistant breast tumors.

Biotinylated platinum(IV) complexes designed to target cancer cells.

Three biotinylated platinum(IV) complexes (1-3) were designed and synthesized. The resulting platinum(IV) complexes exhibited effective cytotoxicity against the tested cancer cell lines, especially complex 1, which was 2.0-9.6-fold more potent than cisplatin. These complexes were found to be rapidly reduced to their activated platinum(II) counterparts by glutathione or ascorbic acid under biologically relevant condition. Additional molecular docking studies revealed that the biotin moieties of all Pt(IV) complexes can effectively bind with the streptavidin through the noncovalent interactions. Besides, introduction of the biotin group can obviously promote the cancer cell uptake of platinum when treated with complex 1, particularly in cisplatin-resistant SGC-7901/Cis cancer cells. Further mechanistic studies on complex 1 indicated that it activated the expression of Bax, and induced cytochrome c release from the mitochondria, and finally activated caspase-3.

Biotin-Pt (IV)-indomethacin hybrid: A targeting anticancer prodrug providing enhanced cancer cellular uptake and reversing cisplatin resistance.

A Pt(IV) prodrug (2) composed of cancer-targeting biotin and nonsteroidal anti-inflammatory drug indomethacin in the axial positions of the six-coordinated octahedral geometry derived from cisplatin was developed, which could be highly accumulated in cancer cells more than normal ones and activated by endogenous reducing molecules to release cisplatin and indomethacin moieties simultaneously to inhibit tumor progression synergistically. In vitro assays revealed that 2 exhibited significantly selective inhibition to the tested cancer cell lines and sensitivity to cisplatin resistant cancer cells. Moreover, 2 presented cyclooxygenases inhibition properties to reduce tumor-associated inflammation, reduced the invasiveness of the highly aggressive PC-3 cells, and disrupted capillary-like tube formation in EA.hy926 cells. In all, this study offers a new strategy to enhance sensitivity and reduce toxicity of cisplatin.