Shanshan Song

Design, Synthesis, and Biological Evaluation of a Series of Benzo(de)(1,7)naphthyridin-7(8H)‑ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

RhIII-Catalyzed Redox-Neutral C–H Activation of Pyrazolones: An Economical Approach for the Synthesis of N-Substituted Indoles

A new strategy is reported for the economical synthesis of indoles bearing an N-(3-aminobut-2-enoyl) substituent through Rh(III)-catalyzed redox-neutral C-H activation of pyrazolones and alkynes. This approach utilizes cheap substrates and mild reaction conditions to access a unique class of indoles via a N-N bond oxidative cleavage without loss of the N-terminus, therefore meeting all the atom/step/redox economy principles.

InBr3-Mediated One-Pot Synthesis of 2-(Polyhydroxylatedalkyl)-N-aryl-/-alkylpyrroles from 1,2-Cyclopropa-3-pyranone and Amines

An efficient one-pot synthesis of polyhydroxyalkyl-substituted pyrroles from 1,2-cyclopropa-3-pyranones with primary amines is reported. With 10% of InBr3 as the catalyst, both aryl- and alkylamines as well as various 1,2-cyclopropa-3-pyranones are well tolerated. This method is highly appealing because of its one-pot process, mild reaction conditions, substrate simplicity, and broad substrate scope.

Study on Er3+ emission from the erbium-doped hydrogenated amorphous silicon suboxide film

The erbium-doped hydrogenated amorphous silicon suboxide films containing amorphous silicon clusters were prepared. The samples exhibited photoluminescence peaks at around 750 nm and 1.54 mum, which could be assigned to the electron-hole recombination in amorphous silicon clusters and the intra-4f transition in Er3+, respectively. Correlations between the intensities of these two photoluminescence peaks and oxidation and dehydrogenation of the films during annealing were studied. It was found that the oxidation is triggered by dehydrogenation of the films even at low annealing temperatures, which decisively changes the intensities of the two photoluminescence peaks. On the other hand, the increase of Er content in the erbium-doped hydrogenated amorphous silicon suboxide film will enhance Er3+ emission at 1.54 mum, while quench amorphous silicon cluster emission at 750 nm, such a competitive relationship, was also observed in the erbium-doped silicon nanocrystals embedded in SiO2 matrix. Moreover, we found that Er3+ emission is not sensitive to whether silicon clusters are crystalline or amorphous. The amorphous silicon clusters can be as sensitizer on Er3+ emission as that of silicon nanocrystals

Total Synthesis of the Marine Cyclic Depsipeptide Viequeamide A

The first total synthesis of viequeamide A, a natural cyclic depsipeptide isolated from a marine button cyanobacterium, was achieved with the N-Me-Val-Thr peptide bond as the final macrocyclization site. The synthetic product gave nearly identical spectroscopic data to that reported for the natural product.

Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolides inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. Mol Cancer Ther; 15(7); 1495–503. ©2016 AACR.

Design, synthesis, and anticancer activities of new compounds bearing the quinone–pyran–lactone tricyclic pharmacophore

A simple and more effective four-step synthesis of the tricyclic quinone–pyran–lactone skeleton was developed. Subsequent structural modification led to several series of derivatives. Regio- and diastereo-characteristics of these compounds were elucidated, and their antitumor activities against several cancer cells were investigated.

Raman scattering and photoluminescence studies of Er-implanted and Er+O coimplanted GaN

Raman measurements and photoluminescence (PL) were performed on the metal-organic chemical-vapor deposition epitaxially grown GaN before and after the implantation with Er and Er+O. Several Raman defect modes have emerged from the implantation-damaged samples. The structures around 300 and 595 cm(-1) modes are attributed to the disorder-activated Raman scattering, whereas the 670 cm(-1) peak is assigned to nitrogen-vacancy-related defect scattering. One additional peak at 360 cm(-1) arises after Er+O coimplantation. This Raman peak is attributed to the O-implantation-induced defect complex. The appearance of the 360 cm(-1) mode results in the decrease of the Er3+ -related infrared PL intensity for the GaN:Er+O samples

Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.

The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced γH2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and γH2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%~100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.

Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties

The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice.