(Acetoxy)(2-methylphenyl)methyl acetate

In the title compound, C12H14O4, the two acet­oxy groups are inclined by 57.92 (5)° and 62.71 (6)° to the benzene ring. An inter­molecular C—H⋯O inter­action involving the two acet­oxy groups generates a centrosymmetric dimer via an R 2 2(16) ring motif

Methyl 3-(4-isopropyl­phen­yl)-1-phenyl-3,3a,4,9b-tetra­hydro-1H-chromeno[4,3-c]isoxazole-3a-carboxyl­ate

In the title compound, C27H27NO4, the five-membered isoxazole ring adopts an envelope conformation and the six-membered pyran ring adopts a half-chair conformation. The dihedral angle between the mean planes of the isoxazole ring and the chromene ring system is 54.95 (4)°

Methyl 6-(4-chloro­phen­yl)-2,4-dimethyl-1,3-dioxo-1,2,3,4,6,6a,7,12b-octa­hydro­chromeno[4′,3′:4,5]pyrano[2,3-d]pyrimidine-6a-carboxyl­ate

In the title compound, C24H21ClN2O6, the two fused six-membered pyran rings adopt half-chair conformations. The dihedral angle between the pyrimidine ring and the chloro­phenyl ring is 51.55 (3)°. In the crystal, mol­ecules are linked by pairs of weak inter­molecular C—H⋯O hydrogen bonds, forming inversion dimers. A C—H⋯π inter­action is also observed

2-(4-Methyl­phen­yl)-1-phenyl­sulfonyl-3-nitro-1,2-dihydro­quinoline

In the title compound, C22H18N2O4S, the dihedral angle between the phenyl­sulfonyl ring and the methyl­phenyl ring is 67.78 (7)°. In the crystal, mol­ecules are linked by weak inter­molecular C—H⋯O inter­actions into a zigzag chain along the [101] direction

7-Phenyl­sulfonyl-2,3-dihydro-7H-1,4-benzodioxino[6,7-b]carbazole

In the title compound, C24H17NO4S, the phenyl ring makes a dihedral angle of 88.12 (5)° with the carbazole unit. The mol­ecular structure is stabilized by weak intra­molecular C—H⋯O inter­actions and the crystal packing exhibits weak inter­molecular C—H⋯O and C—H⋯π inter­actions. Two C atoms of the 2,3-dihydro-1,4-dioxine fragment are disordered over two positions with site-occupancy factors of 0.718 (11) and 0.282 (11)

3,4-Dibromo-2,5-dimethyl-1-phenyl­sulfonyl-1H-pyrrole

In the title compound, C12H11Br2NO2S, the dihedral angle between the two rings is 78.79 (12)°. The crystal packing features C—H⋯π inter­actions

Exploring excited states of Pt(ii) diimine catecholates for photoinduced charge separation

The intense absorption in the red part of the visible range, and the presence of a lowest charge-transfer excited state, render Platinum(II) diimine catecholates potentially promising candidates for light-driven applications. Here, we test their potential as sensitisers in dye-sensitised solar cells and apply, for the first time, the sensitive method of photoacoustic calorimetry (PAC) to determine the efficiency of electron injection in the semiconductor from a photoexcited Pt(II) complex. Pt(II) catecholates containing 2,2′-bipyridine-4,4′-di-carboxylic acid (dcbpy) have been prepared from their parent iso-propyl ester derivatives, complexes of 2,2′-bipyridine-4,4′-di-C(O)OiPr, (COOiPr)2bpy, and their photophysical and electrochemical properties studied. Modifying diimine Pt(II) catecholates with carboxylic acid functionality has allowed for the anchoring of these complexes to thin film TiO2, where steric bulk of the complexes (3,5-ditBu-catechol vs. catechol) has been found to significantly influence the extent of monolayer surface coverage. Dye-sensitised solar cells using Pt(dcbpy)(tBu2Cat), 1a, and Pt(dcbpy)(pCat), 2a, as sensitisers, have been assembled, and photovoltaic measurements performed. The observed low, 0.02–0.07%, device efficiency of such DSSCs is attributed at least in part to the short excited state lifetime of the sensitisers, inherent to this class of complexes. The lifetime of the charge-transfer ML/LLCT excited state in Pt((COOiPr)2bpy)(3,5-di-tBu-catechol) was determined as 250 ps by picosecond time-resolved infrared spectroscopy, TRIR. The measured increase in device efficiency for 2a over 1a is consistent with a similar increase in the quantum yield of charge separation (where the complex acts as a donor and the semiconductor as an acceptor) determined by PAC, and is also proportional to the increased surface loading achieved with 2a. It is concluded that the relative efficiency of devices sensitised with these particular Pt(II) species is governed by the degree of surface coverage. Overall, this work demonstrates the use of Pt(diimine)(catecholate) complexes as potential photosensitizers in solar cells, and the first application of photoacoustic calorimetry to Pt(II) complexes in general

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

Intratumoral Hydrogen Peroxide With Radiation Therapy in Locally Advanced Breast Cancer: Results From a Phase 1 Clinical Trial.

Purpose Hydrogen peroxide (H2O2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral H2O2 + external beam RT as a novel combination in patients with breast cancer and exploratory plasma marker analyses investigating possible mechanisms of action.Methods and materials Twelve patients with breast tumors ≥3 cm (surgically or medically inoperable) received intratumoral H2O2 with either 36 Gy in 6 twice-weekly fractions (n = 6) or 49.5 Gy in 18 daily fractions (n = 6) to the whole breast ± locoregional lymph nodes in a single-center, nonrandomized study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimize local discomfort. The mixture was injected intratumorally under ultrasound guidance twice weekly 1 hour before RT. The primary endpoint was patient-reported maximum intratumoral pain intensity before and 24 hours postinjection. Secondary endpoints included grade ≥3 skin toxicity and tumor response by ultrasound. Blood samples were collected before, during, and at the end of treatment for cell-death and immune marker analysis.Results Compliance with H2O2 and RT was 100%. Five of 12 patients reported moderate pain after injection (grade 2 Common Terminology Criteria for Adverse Events v4.02) with median duration 60 minutes (interquartile range, 20-120 minutes). Skin toxicity was comparable to RT alone, with maintained partial/complete tumor response relative to baseline in 11 of 12 patients at last follow-up (median 12 months). Blood marker analysis highlighted significant associations of TRAIL, IL-1β, IL-4, and MIP-1α with tumor response.Conclusions Intratumoral H2O2 with RT is well tolerated with no additional toxicity compared with RT alone. If efficacy is confirmed in a randomized phase 2 trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor