B e n z i m i d a z o l e s i n O n e S t e p f r o m oN i t r o a n i l i n e s a n d A l d e h y d e s

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.Parkinson's disease | target validation | neuroprotection

No abstract

Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

No abstract

Supported ionic liquid phase (SILP) systems were prepared by immobilizing a methylimidazolium cation based ionic liquid onto the pore surface of two types of support, MCM-41 and Vycor. The "grafting to" method was applied, involving (3-chloropropyl)-trialkoxysilane anchoring on the supports' silanol groups, followed by treatment with 1-methylimidazole and ion exchange with PF(6)(-). Optimum surface pretreatment procedures and reaction conditions for enhanced ionic liquid (IL) loading were properly defined and applied for all modifications. A study on the effect of different pore sizes on the physical state of the grafted 1-(silylpropyl)-3-methylimidazolium-hexafluorophosphate ([spmim][PF(6)(-)]) was also conducted. The [spmim][PF(6)(-)] crystallinity under extreme confinement in the pores was investigated by modulated differential scanning calorimetry (DSC) and X-ray diffraction (XRD) and was further related to the capacity of the developed SILP to preferentially adsorb CO(2) over CO. For this purpose, CO(2) and CO absorption measurements of the bulk ionic liquid [bmim][PF(6)(-)] and the synthesized alkoxysilyl-IL were initially performed at several temperatures. The results showed an enhancement of the bulk IL performance to preferentially adsorb CO(2) at 273 K. The DSC analysis of the SILPs revealed transition of the melting point of the grafted alkoxysilyl-IL to higher temperatures when the support pore size was below 4 nm. The 2.3 nm MCM-41 SILP system exhibited infinite CO(2)/CO separation capacity at temperatures below and above the melting point of the bulk IL phase, adsorbing in parallel significant amounts of CO(2) in a reversible manner. These properties make the developed material an excellent candidate for CO(2)/CO separation with pressure swing adsorption (PSA) techniques.

Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives.

Morphine (la) and its derivatives and analogs continue to hold the fascination of chemists and neuroscientists.' For the synthetic chemist, this small molecule offers an interesting challenge.2 Its intrinsic complexity arises from the presence of five contiguous chiral centers, four of which defme the ring junctions. The problem of establishing these chiral centers is especially difficult because the C-13 center is quaternary and bears an aryl ~ubstituent.~.~Our approach to the construction of the morphine ring system is based on a tandem cyclization of an ortho allyloxy aryl radicaLs We are now pleased to report the short (1 1 steps from commercial ( 2 ) For a recent formal total synthesis and many references to much of the previous work on this problem, scc: Tius, M. A.; Kerr, M. A. J. Am. Chem. Soc. 1992, 114, 5959. In addition, see: Magnus, P.; Coldham, I. J. Am. Chem. Soc. 1991, 113,672. ( 3 ) (a) Rieke, R. D.; Schulte, L. D.; Dawson, B. T.; Yang, S. S. J. Am. Chem. Soc. 1990,112,8388. (b) Lee, E.; Shin, 1.-J.; Kim, T.4. J. Am. Chem. Soc. 1990, 112, 260 and references therein.(4) (a) The intramolecular Heck reaction has been shown to be an efficient method for the generation of a quaternary center which bears an aryl group; see Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987,52,4130. (b) The use of this methodology for the preparation of dihydrothebainone was recently reprted by Overman at the 9th International Conference on Organic Synthesis, Montreal, Quebec, Canada, July 1992. ( 5 ) (a) Parker, K. A.; Spero, D. M.; Inman, K. C. Tetrahedron Lett. 1986, 27,2833. (b) Parker, K. A.; Spero, D. M.; Van Epp, J. J. Org. Chem. 1988, 53, 4628. (c) Parker, K. A.; Fokas, D. Submitted for publication. Scheme I. Strategy for the Synthesis of the Morphine Alkaloids" Me 0 Me 0 2 dihydroisocodeine 3 dihydrocodeinone 1 r-2 r-3 r-1 "(a) Bu3SnH, AIBN, C6H6. 130 OC, 35 h, 35% of 5 (R = H ) from 4b (R = H). (b) Li, t-BuOH, NH3, THF, -78 OC, 10 min, 85%. (c) (COCI)2, DMSO, 0 ' C to room temperature, 2.5 h, 83%. scheme nn &TSAH oAN. TsL Ye a Me0 0 6 9 c:: : : : e Me ye Mea* 1 -N-Ts 1 0 1 1 g c ' b R -H R I TBDMS Ho k S P h Br 12, h -4 , L', RR==Tp"S "(a) Li/NH3, t-BuOH, -6 8 O C , 97%. (b) TsC1, NEt,, THF, then 1 N HCI, 81%. (c) MeI, K2C03, acetone, 96%. (d) NaBH,, CeCI,, MeOH, 0 O C , 97%. (e) m-CPBA, CH2CI2, 0 OC, 92%. (f) Ti(OiPr),, C6H6, 7 0 OC, 85%. (8) TBDMSOTf, i-Pr2NEt, -78 OC, 82%. (h) PBu3, DEAD, THF, 0 OC, 83%. (i) 10% HF, CH3CN, 98%.materials), convergent, and stereospecific synthesis of (f)-dih y d r o i d e i n e (2).6 Oxidation to dihydrocodeinone (3) completes the formal total synthesis of (*)-morphine (Scheme I).By analogy to transformations in our model studies,5bvc we predicted that aryl ether 4 would undergo tandem closure to tetracyclic styrene 5 via an intramolecular tandem cyclization. We expected the (2-12 aryl radical (r-1), derived from substrate 4, to attack the nearer but more substituted end of the cyclohexene double bond, generating the 5-membered dihydrofuran ring and establishing the des...