- Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs
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Abstract: The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake. Graphic abstract: [Figure not available: see fulltext.]
- Hoeschele, James D.,Kasparkova, Jana,Kostrhunova, Hana,Novakova, Olga,Pracharova, Jitka,Pineau, Paul,Brabec, Viktor
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Read Online
- Polycyclic amide derivative as CDK9 inhibitor, and preparation method and application thereof
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The invention belongs to the technical field of polycyclic amide derivatives, and particularly relates to a polycyclic amide derivative as a CDK9 inhibitor, and a preparation method and application thereof. The polycyclic amide derivative shows excellent CDK9 enzyme inhibitory activity, and can be used for preparing drugs for treating cancers, especially hematologic cancers including acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, follicular lymphoma and the like and solid tumors, such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia and follicular lymphoma, including breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, kidney cancer, stomach cancer, colorectal cancer, lung cancer and the like.
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Paragraph 0265-0269
(2021/07/24)
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- TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation
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TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here, we report (1S,3R)-3-((4-(6-methylbenzo[d]
- Qiu, Yunguang,Huang, Lu,Fu, Jie,Han, Chenxia,Fang, Jing,Liao, Ping,Chen, Zhuo,Mo, Yiqing,Sun, Peihua,Liao, Daqing,Yang, Linghui,Wang, Jing,Zhang, Qiansen,Liu, Jin,Liu, Feng,Liu, Tingting,Huang, Wei,Yang, Huaiyu,Jiang, Ruotian
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p. 3665 - 3677
(2020/04/30)
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- Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists
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2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [35S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([35S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
- Geyer, Roland,Nordemann, Uwe,Strasser, Andrea,Wittmann, Hans-Joachim,Buschauer, Armin
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supporting information
p. 3452 - 3470
(2016/05/19)
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- BENZAMIDE IMIDAZOPYRAZINE BTK INHIBITORS
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Provided are Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, or their use in therapy.
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Page/Page column 57; 58
(2016/07/27)
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- Complexation of tetrakis(acetato)chloridodiruthenium with naphthyridine-2,7-dicarboxylate - Characterization and catalytic activity
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The reaction of calcium naphthyridine-2,7-dicarboxylate (Cadcnp) with Ru2(OAc)4Cl in water resulted in the formation of Ca[Ru2(dcnp)(OAc)3]2 (3). X-ray crystal structural analysis of 3 confirmed its molecular structure and showed that the calcium ion binds to the lateral carboxylate groups of four neighboring anionic units of [Ru2(dcnp)(μ-OAc)3] and two acetone molecules to form a two-dimensional framework. The RuII-RuII valence state of the diruthenium core was supported by superconducting quantum interference device (SQUID) magnetometry [μeff (300 K) = 2.77 μB]. Complex 3 appears to be an efficient catalyst for the oxidative cleavage of olefins in aqueous media under mild conditions. Typically, the reaction of pulegone with NaIO4 in water catalyzed by 3 (1 mol-%) at 45 C afforded 3-methyladipic acid quantitatively. The reaction of calcium naphthyridine-2,7-dicarboxylate (Cadcnp) with Ru2(OAc)4Cl provides Ca[Ru2(dcnp)(OAc)3]2 as the exclusive product. The complex is catalytically active for the oxidative cleavage of olefins in aqueous media.
- Lee, Chia-Han,Wu, Cai-Ling,Hua, Shao-An,Liu, Yi-Hung,Peng, Shie-Ming,Liu, Shiuh-Tzung
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p. 1417 - 1423
(2015/03/18)
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- COMPOUNDS AND THEIR METHODS OF USE
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Compounds and compositions comprising compounds that inhibit glutaminase are described herein. Also described herein are methods of using the compounds that inhibit glutaminase in the treatment of cancer.
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- COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND USES AS GLUTAMINASE INHIBITORS FOR TREATING CANCERS THEREOF
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Provided are compounds of formula (I), wherein X, Y, Z, W, m, n, o, p, R1, R2 and R6 are defined as in the description. Pharmaceutical compositions and uses as glutaminase inhibitors for treating cancers thereof are also provided.
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- COMPOUNDS AND THEIR METHODS OF USE
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Provided are compounds of formula (I), which can inhibit glutaminase. Pharmaceutical compositions comprising these compounds and uses as glutaminase inhibitors for treating cancers thereof are also provided.
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- HYDROXAMIC ACID DERIVATIVES AND THEIR USE IN THE TREATMENT OF BACTERIAL INFECTIONS
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Antibacterial compounds of Formula I are provided: as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; use of such compounds in the treatment of bacterial infections and processes for the preparation of such compounds.
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Page/Page column 77; 78
(2012/12/13)
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- SUBSTITUTED DIAMINOCARBOXAMIDE AND DIAMINOCARBONITRILE PYRIMIDINES, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are Diaminopyrimidine Compounds having the following structures: wherein R1, R2, R3, and R4 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidine Compound, and methods for treating or preventing liver fibrotic disorders or a condition treatable or preventable by inhibition of a JNK pathway.
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Page/Page column 179
(2012/11/07)
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- Liquid-phase catalytic oxidation of C6-C7 cycloolefins into carboxylic acids in a pseudohomogeneous system
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Liquid-phase oxidation of cyclohexene, methylcyclohexene isomers, and norbornene with a 30% solution of hydrogen peroxide in a pseudohomogeneous system involving highly dispersed compounds of Group-VIb and -VIIIb metals supported by nanosize carbon particles was studied.
- Alimardanov, Kh. M.,Sadygov,Garibov,Abbasov,Abdullaeva, M. Ya.,Dzhafarova
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experimental part
p. 236 - 242
(2011/06/09)
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- Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N -{2-[4-(2-methoxyphenyl)piperazin-1-yl] ethyl}- N -(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A receptor
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Here we describe the design, synthesis, and pharmacological profile of 5-HT1A receptor ligands related to 1 (WAY-100635). The cyclohexyl moiety in 1 and its O-desmethylated analogue 3 were replaced by the bridgehead iodinated bridge-fused rings: adamantyl, cubyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptyl. All analogues displayed a (sub)nanomolar affinity for the 5-HT1A receptor in vitro. Compounds 6b and 7b appeared to be selective for this receptor over other relevant receptors and could easily be iodinated with radioactive iodine-123. In humane hepatocytes, [ 123I]6b showed a low propensity for amide hydrolysis and a stable carbon-iodine bond. The biodistribution of [123I]6b and [ 123I]7b in rats revealed that the carbon-iodine bond was also stable in vivo. Unfortunately, the brain uptake and the specificity for both radioligands were significantly lower than those of the parent molecule 1. In conclusion, the designed tracers are not suitable for SPECT imaging.
- Al Hussainy, Rana,Verbeek, Joost,Van Der Born, Dion,Braker, Anton H.,Leysen, Josée E.,Knol, Remco J.,Booij, Jan,Herscheid
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supporting information; experimental part
p. 3480 - 3491
(2011/07/07)
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- Tetrapropylammonium perruthenate catalyzed glycol cleavage to carboxylic (Di)acids
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A new method to accomplish glycol cleavage to carboxylic (di)acids in one step using catalytic amounts of tetrapropylammonium perruthenate (TPAP) together with N-methylmorpholine N-Oxide (NMO) as the stoichiometric oxidant is presented. In addition to regenerating the active catalyst, the N-oxide stabilizes intermediary carbonyl hydrates and thereby shifts a crucial equilibrium. The mild oxidation protocol is applicable to a broad range of substrates providing the respective acids, diacids, or keto acids in high yields.
- Schmidt, Andrea-Katharina C.,Stark, Christian B. W.
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supporting information; experimental part
p. 5788 - 5791
(2011/12/05)
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- Catalytic oxidative cleavage of olefins by RuO4 organic solvent-free under ultrasonic irradiation
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All the works reported about oxidative cleavage of olefins by the RuCl3/NaIO4 catalytic system have been performed in biphasic water/organic solvent(s). The first organic solvent-free oxidation of C{double bond, long}C double bond by 2% RuCl3/4.1 equiv NaIO4/H2O is described here using both the emulsifier Aliquat 336 and 20 kHz ultrasonic irradiation.
- Rup, Sandrine,Sindt, Michèle,Oget, Nicolas
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scheme or table
p. 3123 - 3126
(2010/08/07)
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- HETEROBICYCLIC METALLOPROTEASE INHIBITORS
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The present invention relates generally to amide group containing pharmaceutical agents, and in particular, to amide containing heterobicyclic metalloprotease inhibitor compounds. More particularly, the present invention provides a new class of heterobicyclic MMP- 13 inhibiting compounds, that exhibit an increased potency in relation to currently known MMP- 13 inhibitors.
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Page/Page column 167
(2008/06/13)
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- Aryl sulfones: A new class of γ-secretase inhibitors
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The development of a novel series of 4-aryl, 4-phenylsulfonyl cyclohexananone-derived γ-secretase inhibitors for the potential treatment of Alzheimer's disease is described.
- Teall, Martin,Oakley, Paul,Harrison, Timothy,Shaw, Duncan,Kay, Euan,Elliott, Jason,Gerhard, Ute,Castro, Jose L.,Shearman, Mark,Ball, Richard G.,Tsou, Nancy N.
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p. 2685 - 2688
(2007/10/03)
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- Ruthenium catalysed oxidation without CCl4 of oleic acid, other monoenic fatty acids and alkenes
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Ruthenium catalysed oxidation of alkenes and monoenic fatty acids is reported. The study of the influence of cosolvents (H2O/MeCN/X) shows that toxic CCl4 initially used in the Sharpless system (H 2O/MeCN/CCl4) can be avoided and demonstrates that the oxidative cleavage of CC bond could be accomplished in good yields with H 2O/MeCN/AcOEt solvent system in a ratio 3/2/2, respectively.
- Zimmermann, Fran?ois,Meux, Eric,Mieloszynski, Jean-Luc,Lecuire, Jean-Marie,Oget, Nicolas
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p. 3201 - 3203
(2007/10/03)
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- Synthesis and antiviral activities of some novel carbocyclic nucleosides
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cis-3-Aminomethylcyclopentylmethanol (4), prepared from norbornene (5) in four steps and 51% overall yield, was used as a precursor in the synthesis of carbocylic nucleosides 13 - 18 containing guanine and 8-azaguanine bases. None of these compounds had a
- Carmen Balo,Fernandez, Franco,Lens, Evangelina,Lopez, Carmen,De Clercq, Erik,Andrei, Graciela,Snoeck, Robert,Baizarini, Jan
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p. 1335 - 1346
(2007/10/03)
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- Unusual Stereochemical Results in the Reaction of Alpha-Lithio Derivatives of Bicyclic Sulfoxides
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The stereochemistry of the reaction of the lithio derivatives of two sets of isomeric 3-thiaoctane-3-oxides with electrophiles such as benzyl bromide, acetone and D2O has been studied.Introduction of deuterium always occurred cis to the S=O bond as expected on the basis of earlier results described by Marquet for the related thiane-S-oxides.In contrast, benzyl groups were introduced either cis or trans to the existing S=O bond.The results are most readily rationalized in terms of a planar configuration at the α-carbanion center. the unexpected cis benzylations are due to steric hindrance of the preferred approach anti to the S=O bond by either the ethano bridge or the 8-endo methyl group.
- Ben, Robert N.,Breau, Livain,Bensimon, C.,Durst, T.
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p. 6061 - 6076
(2007/10/02)
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- Preparation of Bicycloalkanes by Electrochemical Reduction of 1,3-Dibromocycloalkanes
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Good yields of bicyclo pentane (17) and bicyclo-hexane(3) are obtained on electroreduction of the corresponding 1,3-dibromocycloalkanes.The results do not depend upon the stereochemistry of the starting material (14 vs. 15 or 11 vs. 12).Key Words: Electrochemical reduction / Bicycloalkanes / Cycloalkanes, 1,3-dibromo / Hunsdiecker reaction / 1,3-Cycloalkanedicarboxylic acids
- Hoffmann, Joachim,Voss, Juergen
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p. 1415 - 1420
(2007/10/02)
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- Enantioselective synthesis of (+) and (-)-cis-3-aminocyclopentanecarboxylic acids by enzymatic asymmetrization
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Both enantiomers of cis-3-aminocyclopentanecarboxylic acid (GABA analogs, inhibitory neurotransmitter) have been prepared via enzymatic asymmetrization of cis -1,3-cyclopentanedicarboxylic acid.
- Chenevert,Martin
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p. 199 - 200
(2007/10/02)
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- (Lig)Ni(0) induced preparation of mono- and dicarboxylic acids from cyclopentene and carbon dioxide
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Cyclopentene is shown to be an ideal substrate for coupling reactions with (Lig)nickel(0) systems. By variation of the ligands and addition of promoters, it is possible by successive application of carbon dioxide or carbon monoxide to prepare highly selectively series of cyclopentane- and cyclopentenecarboxylic acids (six examples), 4, 5, 6, 11, 14, 15, cyclopentanedicarboxylic acids (three examples), 7, 8, 12, or 2-hydroxycyclopentanecarboxylic acid (9) in good yields. The C5-skeleton is retained in the products.
- Hoberg,Ballesteros,Sigan,Jegat,Milchereit
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p. 395 - 398
(2007/10/02)
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- Oxidative Cleavage of Vicinal Diols at the Nickel Hydroxide Electrode
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Vicinal diols are oxidatively cleaved with good yields by electrolysis at an oxide covered nickel electrode in an aqueous alkaline electrolyte and an undivided cell.The method is applied in the synthesis of optical pure derivatives of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid.
- Ruholl, Heinrich,Schaefer, Hans J.
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- Indirect Electrooxidation of Alkohols and Aldehydes by Using a Double Mediatory System Consisting of RuO4/RuO2 and Cl+/Cl- Redoxes in an Aqueous-Organic Two-Phase System
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A double mediatory system consisting of RuO4/RuO2 and Cl+/Cl- redox couples has been developed for the indirect electrooxidation of alcohols and aldehydes.The reaction proceeds in the following manner: (1) oxidation of the substrate with ruthenium tetraoxide (RuO4) in the organic layer, (2) regeneration of ruthenium tetraoxide from ruthenium dioxide (RuO2) with active chlorine species (Cl2 or +), and (3) oxidation of chloride ion to + on the anode in the aqueous layer.The range of applicability of the present procedure is discussed by oxidations of (1)secondary alcohols to ketones, (2) primary alcohols and aldehydes to carboxylic acid, (3) 1,n-diols to lactones and keto acids, and (4) carbohydrate derivatives.
- Torii, Sigeru,Inokuchi, Tsutomu,Sugiura, Toyoyuki
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p. 155 - 161
(2007/10/02)
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- Catalytic cis to trans Conversions; Dihydroxybicycloheptane and 1,2-Dihydroxyindane
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cis-2-exo,3-exo-Dihydroxybicycloheptane (2) was isomerized in aqueous solution by an improved procedure to the corresponding trans-glycol 3 in 71percent yield, using Raney nickel at 80 deg C for 56 hours.Similarly, cis-1,2-dihydroxyindane (5) was isomerized by Raney nickel at 60 deg C in 42 hours giving 31percent trans-1,2-dihydroxyindane (7).
- Taylor, Jay E.
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p. 1142 - 1144
(2007/10/02)
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- Synthesis of Bridgehead-Bridgehead Substituted Bicycloalkanes
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A convenient synthetic route to several bicycloalkanes bearing substitution at both bridgehead positions is described.The two-step procedure, which involves alkylation of the monoenolates of readily available cyclohexane diesters with 1,2-dihaloethane followed by a base-inducted cyclization of the derived haloethylated product, was successfully applied to the synthesis of dimethyl bicyclooctane-1,4-dicarboxylate, dimethyl bicycloheptane-1,4-dicarboxylate and dimethyl bicyclooctane-1,5-dicarboxylate.Additionally, it was found that the two latter diesters could be obtained in quite acceptable yields in a one-pot procedure through their corresponding cyclohexyl bisenolate precursors.
- Della, Ernest W.,Tsanaktsidis, John
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p. 1705 - 1718
(2007/10/02)
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- 1,1-Alkanediol dicarboxylate linked antibacterial agents
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Useful antibacterial agents in which a penicillin and/or a beta-lactamase inhibitor are linked via 1,1-alkanediol dicarboxylates are of the formula STR1 where A is the residue of certain dicarboxyic acids, R3 is H or (C1 -C3), n is zero or 1 such that when n is zero R is P or B and R1 is the residue of certain esters, H or a salt thereof; and when n is 1, one of R and R1 is P and the other is B, and P is STR2 where R2 is H or certain acyl groups, and B is the residue of a beta-lactamase inhibiting carboxylic acid; a method for their use, pharmaceutical compositions thereof and intermediates useful in their production.
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- Degenerate Thermal Rearrangement of 1,3-Dimethylenecyclopentane. Evidence for Partially Stereospecific Biradical Formation and Closure in 1,3 Shift
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Parolysis of 1,3-bis(dideuteriomethylene)cyclopentane at 370 deg C resulted in a first-order degenerate rearrangement in which the 1,3- and 3,3-shift products were formed in a 2:1 ratio, respectively, indicating the intermediacy of an effectively orthogonal 2,2'-bis(allylmethane) biradical.Pyrolysis of trans- and cis-4,5-dimethyl-1,3-dimethylenecyclopentane (T and C) gave 1,3- and 3,3-shift products with stereochemistry consistent with predominant conrotatory-bevel ring opening to produce the orthogonal diradical directly.Pyrolysis of optically active T gave the 1,3-shift products with 20.8percent inversion of configuration of the migrating carbon indicative of partial stereospecific closure of the biradical.Comparative pyrolysis of optically active T and its bis(dideuteriomethylene) derivative revealed no secondary kinetic deuterium isotop effect, but an alternation in the extent of racemization of starting material and amounts of 1,3- and 3,3-shift products indicates a product-determining isotope effect.These data provide further evidence for an intermediate.
- Gajewski, Joseph J.,Salazar, Jose Del C.
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p. 4145 - 4154
(2007/10/02)
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- The 1,3-dimethoxytrimethylene bridge as two latent carboxyl groups: synthesis of cis-isoaposantenic and cis-apocamphoric acids
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The syntheses of cis-cyclopentane-1,3-dicarboxylic acid, cis-cyclohexane-1,3-dicarboxylic acid, cis-isoaposantenic acid, and cis-apochamphoric acid are described.The key step of each synthesis is the bromine oxidation of an appropiate bicyclic compound in which a 1,3-dimethoxytrimethylene bridge is converted into two cis-carboxyl groups.
- Camps, Pelayo,Jaime, Carlos
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p. 2848 - 2852
(2007/10/02)
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