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Sulfones and sulfonamides with an α-CH bond can be easily alkylated by aliphatic alcohols to add the carbon skeleton of the alcohol via a one-step, Ru(II) catalyzed redox neutral reaction. The reaction requires a sub-stoichiometric amount of base and produces only water as a byproduct. A number of pharmaceutically relevant functional groups such as piperidine, morpholine, etc. are well tolerated under the reaction conditions to give higher value-added products in one step from widely available substrates. The reaction proceeds through a sulfone carbanion addition to an in-situ generated aldehyde formed via catalytic dehydrogenation and subsequent catalyst mediated replacement of the secondary alcohol by hydrogen.

The large-scale synthesis of heterobifunctional polyethylene glycols (PEGs) with tightly controlled molecular weights ranging from 2 to 20 kDa is described. PEGs were prepared by the ring-opening polymerization of ethylene oxide (EO) initiated from a protected amine ( N -dibenzyl), and a protected alcohol ( O -trityl) initiator. Additionally, EO polymerizations from initiators bearing azide and alkyne, both prototypical “click” chemistry functionalities, are outlined. This demonstrates the first successful use of an initiator bearing either an azide or strained cycloalkyne functionality in an ethylene oxide polymerization. The key to the methodology proved to be the selection of base. The use of potassium naphthalenide or potassium hydride in paraffin wax was highly dependent on the initiator used.

Azido‐functionalized poly(ethylene glycol) (PEG) derivatives are finding ever‐increasing applications in the areas of conjugation chemistry and targeted drug delivery by their judicious incorporation into nanoparticle‐forming polymeric systems. Quantification of azide incorporation into such PEG polymers is essential to their effective use. 1H Nuclear Magnetic Resonance (NMR) analysis offers the simplest approach; however, the relevant adjacent azide‐bearing methylene protons are often obscured by the PEG manifold signals. This study describes the synthesis of 1,2,3‐triazole adducts from their corresponding PEG azides via a convenient, mild click reaction, which facilitates straightforward NMR‐based quantitative end‐group analysis.This method was found to be compatible with many examples of bifunctional azido PEGs with molecular weights ranging from 2 to 18 kDa bearing a variety of functional groups. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 2888–2895

Rho kinase (ROCK) is currently investigated as a target for various diseases such as glaucoma and spinal cord injury. Herein, we report the asymmetric synthesis of chroman 1, a highly potent ROCK inhibitor, and its analogs. The inhibitory properties of these compounds for ROCK-II and a selected set of highly homologous kinases are also discussed.

IT-141 is a formulation of SN-38 encapsulated in an iron-stabilized polymer micelle. SN-38 is the active metabolite of irinotecan (CPT-11) which in combination with 5-FU and leucovorin is first-line FDA approved therapy for metastatic colorectal cancer. Although SN-38 is 1,000 times more potent than irinotecan alone, there is about 100-fold lower concentration of SN-38 in plasma from irinotecan. In the clinic only 2% to 10% of the administered dose of irinotecan is converted by carboxylesterases to SN-38 and there is great interpatient variability with toxicity. In vitro, IT-141 demonstrated nanomolar IC50s against a panel of human cancer cell lines in comparison to irinotecan's micromolar IC50 concentrations. SN-38 binds to the topoisomerase I-DNA complex resulting in double stranded breaks and cell death. We compared the mechanism of action of IT-141 compared to irinotecan treatment in HT-29 xenografts tumors. We demonstrated the incidence of double stranded breaks by immunohistochemistry (IHC) of γ- H2AX expression in tumors treated with IT-141 compared to irinotecan treatment at different time points (24, 48, 72 and 144 hours). In irinotecan treated tumors, γ- H2AX expression peaked at 72 hours followed by a sharp decrease in expression at 144 hours. In IT-141 treated tumors, γ- H2AX positive staining increased steadily from 24 through 144 hours. This shift in the kinetics of the mechanism corroborates the biodistribution studies where IT-141 delivered 34-fold more SN-38 to the tumor compared to irinotecan. The AUC and Cmax in IT-141 treated tumors was 30.9 μg*h/g and 12.2 μg/g respectively compared to an AUC of 1.1 μg*h/g and a Cmax of 0.2 μg/g in the irinotecan treated tumors. In an HT-29 xenograft model IT-141 inhibited tumor growth by 157% compared to a 57% with irinotecan. IT-141 demonstrates successful encapsulation of SN-38 leading to a safer, more effective formulation. Our DNA damage assay demonstrated that IT-141 extended the pharmacodynamic effect over irinotecan in treated tumors. Further studies are required to determine the duration of IT-141's pharmacodynamics effect. This data validates the increased tumor accumulation of SN-38 and increased efficacy of IT-141 over irinotecan. Citation Format: Jyothi Sethuraman, Tara Lee Costich, Adam Carie, Taylor Buley, Tyler Ellis, J. Edward Semple, Tomas Vojkovsky, Kevin Sill, Suzanne Bakewell. IT-141, a stabilized polymer micelle formulation, prolongs the pharmacodynamic effect of SN-38. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B22.

Daunorubicin is an anthracycline family chemotherapeutic with a narrow therapeutic window. Employing our nanoparticle drug delivery platform we encapsulated daunorubicin non-covalently in the hydrophobic core of a polymer micelle (IT-143). IT-143 is a nanoparticle formulation comprised of a hydroxamic acid triblock polymer with ferric crosslinking that increases stability for improved drug circulation and results in a pH dependent release of the encapsulated daunorubicin. Formulation characterization demonstrates a 3.7% weight loading (v/v) of daunorubicin resulting in an average micellar size of 58 nm. In vitro cytotoxicity is comparable to daunorubicin free drug with an IC50 ranging between 60-100 nM, dependent on cell line, compared to 67-114 nM for daunorubicin. In vivo we compared IT-143 plasma pharmacokinetics to daunorubicin administered as free drug and the Cmax was extended from 0.18 μg/mL for daunorubicin to 27.0 μg/mL for IT-143 at the 3 mg/kg dose, and to 49.4 μg/mL at the 6 mg/kg dose. We increased the maximum tolerated dose (MTD) from 7.5 mg/kg to 17.5 mg/kg in mice and improved anti-tumor efficacy. Furthermore, IT-143 eliminated in vivo toxicity compared to equivalent daunorubicin dosed at its MTD. Efficacy studies in 3 xenograft models (HCT116, HT-1080 and HOS-MNNG) compared intravenous bolus administration of IT-143 at equivalent and equitoxic dose to daunorubicin treatment. IT-143 inhibited HCT116 colorectal tumor volume growth by 21% compared to 7% at the equivalent daunorubicin dose, and by 51% at the 17.5 mg/kg dose. In the HT-1080 fibrosarcoma model IT-143 inhibited tumor volume by 38% compared to 37% inhibition at the equivalent daunorubicin dose, and by 94% at the 17.5 mg/kg dose. In the HOS-MNNG osteosarcoma model IT-143 did not inhibit tumor volume compared to 21% inhibition at the equivalent daunorubicin dose, but inhibited tumor volume by 34% at the 17.5 mg/kg dose. The encapsulation of daunorubicin as IT-143 exhibits increased dosage of daunorubicin with decreased toxicities not possible with free daunorubicin. These studies indicate that IT-143 widens the therapeutic window of daunorubicin treatment, providing a safer way to reduce patient toxicity yet increasing antitumor efficacy. Citation Format: Tara Lee Costich, Rick Crouse, Adam Carie, Taylor Buley, Tyler Ellis, Lauren Repp, J.Edward Semple, Tomas Vojkovsky, Suzanne Bakewell, Kevin Sill. IT-143: A nanoparticle delivery platform that encapsulates daunorubicin and widens therapeutic window. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1317.

Site-specific delivery of oncology drugs using nanoparticle technology has been a decades-long goal. IT-141 and IT-147 are polymer micelles that encapsulate (i.e. physically entrap without covalent bonds) hydrophobic chemotherapeutics in the core of the micelle. IT-141 incorporates SN-38, the active moiety of irinotecan, in its core with a weight loading (v/v) of 2%. IT-141 shows increased pharmacokinetics in rat plasma, increased maximum tolerated dose (MTD) and improved anti-tumor efficacy in HCT116 and HT-29 xenograft models over irinotecan in all studies. IT-147 incorporates epothilone D, a microtubule-stabilizing anti-metabolite with a weight loading (v/v) of 2%. IT-147 shows increased pharmacokinetics in rat plasma, increased MTD and improved anti-tumor efficacy in HCT116 colorectal, A549 lung and NCI-H460 lung xenograft models over epothilone D free drug treatment. Both micelles are 70-100 nm diameter clusters of surfactant triblock copolymers stabilized by the interaction between iron and multiple polymer chains. The iron-polymer dative bonds are unstable at low pH, providing a mechanism for environment-dependent micelle stability and subsequent drug release. Furthermore, these stabilized micelles in vivo possess relaxivity constants suitable to provide contrast in magnetic resonance imaging (MRI). The spin-lattice relaxivity value (r1) was 7-16 mM-1s-1 and the spin-spin relaxivity values (r2) were 65-80 mM-1s-1. Small molecule complexes of iron do not typically provide sufficient MR contrast. Because contrast is not observed with individual iron complexes, and the MR contrast is directly related to the properties of the iron-stabilized nanoparticle, only intact nanoparticles provide contrast in MRI. When these iron-stabilized micelle formulations are administered to tumor bearing xenograft mice, increased contrast in the tumor is observed, peaking between 24 and 48 hours. MRI was performed with IT-141 in HCT116, HT-29, and A549 subcutaneous tumor models. IT-147 contrast imaging was performed in HCT116 and NCI-H460 subcutaneous, and MCF-7 orthotopic tumor models. Our technology has produced stable micelles that encapsulate chemotherapeutic drugs to include SN-38, daunorubicin, epothilone D, panobinostat, paclitaxel, and aminopterin with improved pharmacokinetics, decreased toxicity and increased efficacy. The MRI imaging results hold potential for use in the clinic where delivery of the chemotherapeutic-loaded nanoparticle can be monitored non-invasively. Citation Format: Kevin Sill, Tara Lee Costich, Adam Carie, Jyothi Sethuraman, Taylor Buley, Tyler Ellis, Tomas Vojkovsky, Bradford Sullivan, J. Edward Semple, Suzanne Bakewell. IT-141 and IT-147, iron stabilized micellar nanoparticles for therapeutic and diagnostic applications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-190.

IT-139, sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] is a first in class small molecule that has successfully completed a phase I clinical trial against solid refractory cancers. 11 of 41 patients achieved stable disease with manageable side effects and 8 patients showed tumor size reduction including a durable partial response. Preclinical studies suggest IT-139 down-regulates the chaperone GRP78, but the mechanism of action is not fully understood. GRP78 (also known as BiP and HSPA5) is the primary sensor and regulator of the endoplasmic reticulum (ER). In cancer cells it is preferably expressed on the cell surface, but also translocates to the mitochondria and cytosol where it regulates critical oncogenic signaling pathways, thus making GRP78 an excellent target for therapy. Here we show in vitro results of IT-139 treatment in a panel of cancer cell lines. IC50 levels measured at 72 hour varied ranging from 15 μM to 180 μM. Annexin V/PI staining by flow cytometry in HCT-116, HT-29, A375 and A549 cell lines at 24 hour show early and late apoptosis, which corresponds to their relative IC50s. UPR induction and overexpression of GRP78 has been reported to cause cell cycle arrest in G1. But in IT-139 treated cell lines HCT116, HT-29, A549 and LnCAP, cell cycle arrest occurred in G2, whereas in A375 cells IT-139 induced cell cycle arrest at G1. These data suggest an inhibition of GRP78 levels and that cell cycle arrest status is also dependent upon the cell line. Electron microscopic (EM) images of HCT-116 and HT-29 cells treated with IT-139 at 24 hours showed significant vacuolization, ER expansion and disorganization of intracellular organelles, strongly suggesting ER stress. However, there is an absence of double membrane vacuoles or autophagosome formation in response to the ER stress. Also, immunofluorescent analysis displayed no LC3-II punctate distribution, although protein immunoblots showed LC3 and p62 protein levels increasing in IT-139 treated cells. These data suggest an inhibition of autophagy. Additionally, EM images showed vacuolated mitochondria and distortion of cristae. In all cell lines treated with IT-139 even below their corresponding IC50 concentration, JC-1 staining showed an increased loss of mitochondrial membrane potential. These observations hypothetically indicate an inhibition of stress-induced GRP78. Quantitative real-time PCR showed IT-139 treatment in combination with thapsigargin exhibits a significant fold change decrease in the GRP78 mRNA expression. These results suggest that IT-139 downregulates GRP78 leading to an increase in ER stress, mitochondrial damage, decreased autophagy, increased apoptosis and cell death. Citation Format: Jyothi Sethuraman, Tara Lee Costich, Tomas Vojkovsky, Rick Crouse, Valentin Cognet, Suzanne Bakewell. IT-139 targets GRP78 in stressed cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2996.

Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).

(1997). IMPROVED ONE-POT PREPARATION OF TETRAMETHYLFLUOROFORMAMIDINIUM HEXAFLUOROPHOSPHATE. Organic Preparations and Procedures International: Vol. 29, No. 4, pp. 497-498.

The development of enantioselective Lewis acid catalyzed carbonyl addition reactions of π-nucleophiles such as enolsilanes and allylstannanes is a topic of current interest.1 The extension of this general process to include simple olefinic nucleophiles via the carbonyl-ene reaction2 has important practical implications. In this context, Mikami and Nakai have reported a catalytic enantioselective ene reaction with glyoxylate esters;3 however, due to the limiting reactivity of the catalyst-glyoxylate complex,4 only nucleophilic 1,1-disubstituted olefins may be employed. We have recently reported that bidentate bis(oxazolinyl) (box) Cu(II) complexes 1-3 are effective enantioselective catalysts in Diels-Alder5 and aldol reactions6 with substrates that can participate in catalyst chelation. In this study, we demonstrate that

A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors.

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-β, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774–82]

The development of enantioselective Lewis acid catalyzed carbonyl addition reactions of π-nucleophiles such as enolsilanes and allylstannanes is a topic of current interest.1 The extension of this general process to include simple olefinic nucleophiles via the carbonyl-ene reaction2 has important practical implications. In this context, Mikami and Nakai have reported a catalytic enantioselective ene reaction with glyoxylate esters;3 however, due to the limiting reactivity of the catalyst-glyoxylate complex,4 only nucleophilic 1,1-disubstituted olefins may be employed. We have recently reported that bidentate bis(oxazolinyl) (box) Cu(II) complexes 1-3 are effective enantioselective catalysts in Diels-Alder5 and aldol reactions6 with substrates that can participate in catalyst chelation. In this study, we demonstrate that

(1997). IMPROVED ONE-POT PREPARATION OF TETRAMETHYLFLUOROFORMAMIDINIUM HEXAFLUOROPHOSPHATE. Organic Preparations and Procedures International: Vol. 29, No. 4, pp. 497-498.