Fractalkine Receptor Regulates Cellular Response to X-Ray Radiation in Ovarian Cancer Cells

High-grade serous carcinoma (HGSC) is the most common and lethal histotype of ovarian cancer. Radiation is usually used as a second-line treatment against the disease. In spite of numerous clinical studies indicating efficacy of radiation therapy in patients suffering from disease recurrence, it is seldom used clinically due to severe dose-related toxicity. Discovery and utilization of novel radiosensitizers could control the toxicity and enable effective therapeutic application of radiation. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G protein-coupled receptors. Our previous publications showed that CX3CR1 is not expressed in normal ovarian surface epithelium and is expressed in primary and metastatic epithelial ovarian carcinoma. Moreover, transient downregulation of CX3CR1 in ovarian cancer cells will impair their proliferation as well as their migration and adhesion to peritoneal mesothelial cells. Therefore, we proposed combining CX3CR1 downregulation and radiation as a strategy for reducing the dose of radiation while maintaining the therapeutic efficacy. The experimental observations indicated that transient downregulation of CX3CR1 in most HGSC cell lines can lead to radiosensitization, as determined by clonogenic assay. However, loss of CX3CR1 does not affect radiosensitivity in ovarian cancer cells that express wild-type p53. There are several altered characteristics that may contribute to resistance to ionizing radiation, including enhanced DNA damage repair, and adaptive response to the radiation-induced ROS (Reactive Oxygen Species). Specifically, my results indicated that downregulation of CX3CR1 can abrogate the phosphorylation and activation of DNA double-strand break repair related proteins following ionizing radiation. The unrepaired DNA damage leads to damage persistence and ultimately contributes to radiosensitization. Another mechanism by which CX3CR1 knockdown alters radiosensitivity is the regulation of cellular redox capacity, where loss of CX3CR1 leads to elevated ROS levels. Taken together, my study demonstrated for the novel findings that loss of CX3CR1 can sensitize HGSC cells to ionizing radiation through the regulation of DNA damage response and intracellular redox status

Palladium-Catalyzed Diastereo- and Enantioselective Wagner−Meerwein Shift: Control of Absolute Stereochemistry in the C−C Bond Migration Event

Inducing absolute stereochemistry in Wagner−Meerwein shifts was examined in a ring expansion protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities. The results demonstrate that, during the C−C bond migration process, our chiral catalysts can control the stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover, the stereochemical outcome of the reaction can be rationalized very well with the working model of the chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones with an α-chiral O-tertiary center which has various synthetic applications

Palladium-Catalyzed Diastereo- and Enantioselective Wagner−Meerwein Shift: Control of Absolute Stereochemistry in the C−C Bond Migration Event

Inducing absolute stereochemistry in Wagner−Meerwein shifts was examined in a ring expansion protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities. The results demonstrate that, during the C−C bond migration process, our chiral catalysts can control the stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover, the stereochemical outcome of the reaction can be rationalized very well with the working model of the chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones with an α-chiral O-tertiary center which has various synthetic applications

Palladium-Catalyzed Diastereo- and Enantioselective Wagner−Meerwein Shift: Control of Absolute Stereochemistry in the C−C Bond Migration Event

Inducing absolute stereochemistry in Wagner−Meerwein shifts was examined in a ring expansion protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities. The results demonstrate that, during the C−C bond migration process, our chiral catalysts can control the stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover, the stereochemical outcome of the reaction can be rationalized very well with the working model of the chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones with an α-chiral O-tertiary center which has various synthetic applications

Palladium-Catalyzed Asymmetric Ring Expansion of Allenylcyclobutanols: An Asymmetric Wagner−Meerwein Shift

In this study, we developed a palladium-catalyzed atom economic asymmetric Wagner−Meerwein shift of allenylcyclobutanol substrates. It is an excellent method for creating functionalized cyclopentanones with an α-chiral O-tertiary center by ring expansion of allenylcyclobutanols. This reaction was initiated by hydropalladation and afforded excellent enantioselectivity as well as atom economy. This method provides an efficient route toward the synthesis of natural products such as trans-kumausyne's family, spiro ring systems. In addition, we obtained excellent diastereoselectivity and enantioselectivity at the same time by using 3-monosubstituted allenylcyclobutanol

Palladium-Catalyzed Diastereo- and Enantioselective Wagner−Meerwein Shift: Control of Absolute Stereochemistry in the C−C Bond Migration Event

Inducing absolute stereochemistry in Wagner−Meerwein shifts was examined in a ring expansion protocol. Initiated by generation of a π-allylpalladium intermediate by hydropalladation of allenes, the ring expansion of allenylcyclobutanol substrates proceeded with excellent diastereo- and enantioselectivities. The results demonstrate that, during the C−C bond migration process, our chiral catalysts can control the stereochemistry of both the π-allylpalladium intermediate and the corresponding migration bond. Moreover, the stereochemical outcome of the reaction can be rationalized very well with the working model of the chiral catalyst. The method provides an efficient way to synthesize highly substituted cyclopentanones with an α-chiral O-tertiary center which has various synthetic applications

The Palladium Catalyzed Asymmetric Addition of Oxindoles and Allenes: An Atom-Economical Versatile Method for the Construction of Chiral Indole Alkaloids

The Pd-catalyzed asymmetric allylic alkylation (AAA) is one of the most useful and versatile methods for asymmetric synthesis known in organometallic chemistry. Development of this reaction over the past 30 years has typically relied on the use of an allylic electrophile bearing an appropriate leaving group to access the reactive Pd(π-allyl) intermediate that goes on to the desired coupling product after attack by the nucleophile present in the reaction. Our group has been interested in developing alternative approaches to access the reactive Pd(π-allyl) intermediate that does not require the use of an activated electrophile, which ultimately generates a stoichiometric byproduct in the reaction that is derived from the leftover leaving group. Along these lines, we have demonstrated that allenes can be used to generate the reactive Pd(π-allyl) intermediate in the presence of an acid cocatalyst, and this system is compatible with nucleophiles to allow for formation of formal AAA products by Pd-catalyzed additions to allenes. This article describes our work regarding the use of oxindoles as carbon-based nucleophiles in a Pd-catalyzed asymmetric addition of oxindoles to allenes (Pd-catalyzed hydrocarbonation of allenes). By using the chiral standard Trost ligand (L1) and 3-aryloxindoles as nucleophiles, this hydrocarbonation reaction provides products with two vicinal stereocenters, with one being quaternary, in excellent chemo-, regio-, diastereo-, and enantioselectivities in high chemical yields

Stereoselective, Dual-Mode Ruthenium-Catalyzed Ring Expansion of Alkynylcyclopropanols

Stereoselective, Dual-Mode Ruthenium-Catalyzed Ring Expansion of Alkynylcyclopropanol