- Branched alkyl of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as unique cytochrome P450 1A1-activated antimitotic prodrugs: Biological evaluation and mechanism of bioactivation
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We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB–SOs) bioactivatable by cytochrome P450 1A1 (CYP1A1) into potent antimitotics referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs display significant selectivity toward human breast cancer cells based on the N-dealkylation of PAIB-SOs into their corresponding PIB-SOs by CYP1A1. In this study, we have evaluated the molecular mechanism of the bioactivation of PAIB-SOs into PIB-SOs by branching the linear alkyl chain on the imidazolidin-2-one (IMZ) moiety of PAIB-SOs by branched alkyl groups such as isopropyl, isobutyl and sec-butyl. Our results show that PAIB-SOs bearing an isobutyl group on the IMZ moiety and either a methoxy, a chloro or a bromo group at positions 3, 3,5 or 3,4,5 on the aromatic ring B exhibit antiproliferative activity ranging from 0.13 to 6.9 μM and selectivity toward MCF7 and MDA-MB-468 mammary cancer cells comparatively to other cell lines tested. Moreover, the most potent and selective PAIB-SOs bearing an isobutyl group and either a 3,5-Cl (44), 3,5-Br (45) or a 3,4,5-OMe (46) on the IMZ moiety exhibit antiproliferative activity in the sub-micromolar range and high selectivity ratios toward mammary cancer cells. They stop the cell cycle of MCF7 cells in the G2/M phase and disrupt their cytoskeleton. Furthermore, our studies evidenced that PAIB-SOs bearing either an isopropyl, a sec-butyl or an isobutyl group are hydroxylated on the carbon atom adjacent to the IMZ (Cα-OH) but only PAIB-SOs bearing an isobutyl group are bioactivated into PIB-SOs. Finally, PAIB-SOs 45 and 46 exhibit low toxicity toward normal cells and chick embryos and are thus promising antimitotic prodrugs highly selective toward CYP1A1-expressing breast cancer cells.
- Bouzriba, Chahrazed,Chavez Alvarez, Atziri Corin,Gagné-Boulet, Mathieu,Ouellette, Vincent,Lacroix, Jacques,C?té, Marie-France,C.-Gaudreault, René,Fortin, Sébastien
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- Design, Synthesis, and Evaluation of Novel Enterovirus 71 Inhibitors as Therapeutic Drug Leads for the Treatment of Human Hand, Foot, and Mouth Disease
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Human hand, foot, and mouth disease (HFMD) is a serious public health threat with high infection rates in children and infants who reside in Asia and the Pacific regions, and no effective drugs are currently available. Enterovirus 71 (EV71) and coxsackievirus A16 are the major etiological pathogens. Based on an essential hydrophobic pocket on the viral capsid protein VP1, we designed and synthesized a series of small molecular weight compounds as inhibitors of EV71. A potential drug candidate named NLD-22 exhibited excellent antiviral activity (with an EC50 of 5.056 nM and a 100% protection rate for mice at a dose of 20 mg/kg) and low toxicity. NLD-22 had a favorable pharmacokinetic profile. High-resolution cryo-electron microscopy structural analysis confirmed NLD-22 bound to the hydrophobic pocket in VP1 to block viral infection. In general, NLD-22 was indicated to be a promising potential drug candidate for the treatment of HFMD.
- Zhang, Min,Wang, Ying,He, Wanli,Sun, Yao,Guo, Yan,Zhong, Weilong,Gao, Qiang,Liao, Mingyang,Wang, Xiangxi,Cai, Yan,Guo, Yu,Rao, Zihe
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p. 1233 - 1244
(2020/03/10)
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- Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity
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The efficient and catalytic amination of unactivated alkenes with simple secondary alkyl amines is preferentially achieved. A sterically accessible, N,O-chelated cyclic ureate tantalum catalyst was prepared and characterized by X-ray crystallography. This
- Daneshmand, Pargol,Ro?ca, Sorin-Claudiu,Dalhoff, Rosalie,Yin, Kejun,Dipucchio, Rebecca C.,Ivanovich, Ryan A.,Polat, Dilan E.,Beauchemin, André M.,Schafer, Laurel L.
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supporting information
p. 15740 - 15750
(2020/10/18)
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- GROUP 5 METAL COMPLEXES FOR PRODUCING AMINE-FUNTIONALIZED POLYOLEFINS
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This application pertains to group 5 metal complexes having the structure of Formula I: and their potential utility in catalyzing amination of polyolefins having alkene groups.amine-
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Page/Page column 33
(2019/12/15)
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- 4-(3-Alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides as new antimitotic prodrugs activated by cytochrome P450 1A1 in breast cancer cells
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The role and the importance of the sulfonate moiety in phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were assessed using its bioisosteric sulfonamide equivalent leading to new cytochrome P450 1A1 (CYP1A1)-activated prodrugs designa
- Chavez Alvarez, Atziri Corin,Zarifi Khosroshahi, Mitra,C?té, Marie-France,Gagné-Boulet, Mathieu,Fortin, Sébastien
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p. 5045 - 5052
(2018/09/13)
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- GROUP 5 METAL COMPLEXES FOR CATALYTIC AMINE FUNCTIONALIZATION
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This application pertains to group 5 metal complexes having the structure of Formula I; and their potential utility in catalyzing α-alkylation of secondary amine-containing moieties.
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Page/Page column 19; 20
(2018/12/14)
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- Activation of Phenyl 4-(2-Oxo-3-Alkylimidazolidin-1-yl)benzenesulfonates Prodrugs by CYP1A1 as New Antimitotics Targeting Breast Cancer Cells
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Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-Alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) that are antimicrotubule prodrugs activated by CYP1A1. Although PAIB-SOs are inert in most cells tested, they are highly cytocidal toward several human breast cancer cells, including hormone-independent and chemoresistant types. PAIB-SOs are N-dealkylated into cytotoxic phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) in CYP1A1-positive cancer cells, both in vitro and in vivo. In conclusion, PAIB-SOs are novel chemotherapeutic prodrugs with no equivalent among current antineoplastics and whose selective action toward breast cancer is tailored to the characteristic pattern of CYP1A1 expression observed in a large percentage of human breast tumors.
- Fortin, Sébastien,Charest-Morin, Xavier,Turcotte, Vanessa,Lauvaux, Coraline,Lacroix, Jacques,C?té, Marie-France,Gobeil, Stéphane,Gaudreault, René C.
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p. 4963 - 4982
(2017/06/28)
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- CARBAZOLE-CONTAINING AMIDES, CARBAMATES, AND UREAS AS CRYPTOCHROME MODULATORS
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The subject matter herein is directed to carbazole-containing amide, carbamate, and urea derivatives and pharmaceutically acceptable salts or hydrates thereof of structural formula I wherein the variable R1, R2, R3, R4, R5, R6, R7, A, D, E, G, J, L, M, Q, a, and b are accordingly described. Also provided are pharmaceutical compositions containing the compounds of formula I to treat a Cry-mediated disease or disorder, such as diabetes, complications associated with diabetes, Cushing's syndrome, NASH, NAFLD, asthma, and COPD.
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Paragraph 0331
(2015/10/28)
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- SUBSTITUTED 2-IMIDAZOLIDINONES AND 2-IMIDAZOLONES AND THEIR USE IN THE TREATMENT OF CANCER
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Compounds of formula (I) wherein R1, R4, R8, X and Y as defined herein are provided as useful for the inhibition of certain types of cancer cells, amongst others, breast cancer cells, or for the manufacture of anti-cancer
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Paragraph 0070
(2013/03/26)
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- 5-HT RECEPTOR MODULATORS
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The invention relates to compounds of formula (I), useful for treating disorders mediated by the 5-hydroxytryptamine (serotonin) receptor IB (5-HT1B), e.g. vascular disorders, cancer and CNS disorders. The invention also provides methods of treating such disorders, and compounds and compositions etc. for their treatment.
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Paragraph 0613; 0614; 0615
(2013/03/26)
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- Nucleophilic substitution of azide acting as a pseudo leaving group: One-step synthesis of various aza heterocycles
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The reaction of 3-azidopropanoic acid with the carbodiimide-based coupling reagent DIC leads to a six-membered-ring intermediate acting as a versatile precursor to a diverse set of aza heterocycles, including mono-, bi-, and tricyclic compounds.
- Doebelin, Christelle,Schmitt, Martine,Antheaume, Cyril,Bourguignon, Jean-Jacques,Bihel, Frederic
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p. 11335 - 11341
(2013/12/04)
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- Design, synthesis, biological evaluation, and Structure - Activity relationships of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new tubulin inhibitors mimicking combretastatin A-4
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Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are
- Fortin, Sébastien,Wei, Lianhu,Moreau, Emmanuel,Lacroix, Jacques,C?té, Marie-France,Petitclerc, éric,Kotra, Lakshmi P.,C.-Gaudreault, René
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experimental part
p. 4559 - 4580
(2011/09/15)
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- SUBSTITUTED 2-IMIDAZOLIDONES AND ANALOGS
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Compounds of formula (I): wherein R1, R2, R3, R4, R7, R6, R7, R8, R9, A, X and Y as defined herein are provided as useful for the treatment of cancer or for
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Page/Page column 25; 84-85
(2011/09/19)
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- Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships
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The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G2/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.
- Fortin, Sébastien,Wei, Lianhu,Moreau, Emmanuel,Lacroix, Jacques,C?té, Marie-France,Petitclerc, éric,Kotra, Lakshmi P.,Gaudreault, René C.
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experimental part
p. 5327 - 5342
(2012/01/06)
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- Mild, convenient and versatile Cu-mediated synthesis of N-aryl-2-imidazolidinones
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A mild, general, convenient and practical methodology for the selective copper-mediated mono N-arylation of unprotected 2-imidazolidinone was developed. Strong electron-donating groups and free hydroxy and amino groups on the aryl iodide substrates were well tolerated. The use of n-butanol as the solvent for the copper-catalysed mono-arylation of 2-imidazolidinone is unprecedented.
- Stabile, Paolo,Lamonica, Alessandro,Ribecai, Arianna,Castoldi, Damiano,Guercio, Giuseppe,Curcuruto, Ornella
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scheme or table
p. 3232 - 3235
(2010/08/07)
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- 2-ARYLTHIAZOLE DERIVATIVES AS CXCR3 RECEPTOR MODULATORS
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The invention encompasses compounds of Formula I or pharmaceutically acceptable salts thereof, which are modulators of the CXCR3 chemokine receptor function useful for the treatment or prevention of pathogenic inflammatory processes, autoimmune diseases or graft rejection processes. Methods of use and pharmaceutical compositions are also encompassed.
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Page/Page column 50
(2010/11/28)
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- Lithiation of 1-arylimidazol-2(1H)-ones and 1-aryl-4,5-dihydroimidazol- 2(1H)-ones
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1-Arylimidazol-2(1H)-ones are shown to be readily lithiated, using 2 mol equiv. of n-butyllithium, on the benzene ring, ortho to the heterocycle. 1-Aryl-4,5-dihydroimidazol-2(1H)-ones also undergo metalation on the aromatic substitutuent ortho to the heterocycle, but less efficiently. 1-Aryl-3-methylimidazol-2(1H)-ones are lithiated on the heterocyclic ring and then on the benzene ring ortho to the heterocycle. No ortho-directing effect was found for 1-aryl-4,5-dihydro-3-methylimidazol-2(1H)-ones.
- Llopart, Carme Cantos,Ferrer, Conchita,Joule, John A.
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p. 1649 - 1661
(2007/10/03)
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- Investigation of the Mitsunobu reaction of N-(2-hydroxyethyl)-N'- phenyl-ureas
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The Mitsunobu reaction of N-(2-hydroxyethyl)-ureas 1 using PPh3 and EtO2CN=NCO2Et led to the mixture of N- and O-alkylation products or a single isomer depending on the substrates.
- Kim, Taek Hyeon,Lee, Gue-Jae,Cha, Mi-Hyun
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p. 2753 - 2758
(2007/10/03)
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- Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides.
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Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimula
- Parmee,Naylor,Perkins,Colandrea,Ok,Candelore,Cascieri,Deng,Feeney,Forrest,Hom,MacIntyre,Miller,Stearns,Strader,Tota,Wyvratt,Fisher,Weber
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p. 749 - 754
(2007/10/03)
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- Chiral auxiliaries and their use in the synthesis of chiral molecules
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Chiral imidazolidones and imidazolidinethiones having the general formula: STR1 where (a) Z is either oxygen or sulphur (b) the R groups are independently selected from hydrogen or R2 CO where R2 is C1 to C10 alkyl, C2 to C10 alkenyl or benzyl and (c) the two R1 groups are either (1) identical groups selected from C1 to C10 alkyl, phenyl or C1 to C6 alkyl or alkoxy substituted phenyl or (2) such that together they form an alkylene group of formula --(CH2)n -- where n=3 to 8. Most preferred are those compounds where both R groups are R2 CO and there is a C2 axis of symmetry running along the CZ double bond. Compounds of formula (I) where at least one R group is R2 CO are efficient chiral auxiliaries for a range of asymmetric electrophilic substitution reactions when used in homochiral form. As such they are important tools for synthesising a range of chiral pharmaceuticals, agrochemicals and the like.
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- Carbonylation of Amines by Carbon Dioxide in the Presence of an Organoantimony Catalyst
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1,3-Dialkylureas (RNHCONHR; where R = Bu, i-Bu, s-Bu, t-Bu, allyl, Ph) and tetramethylurea were successfully prepared at 80 deg C under an initial CO2 pressure of 4.9 MPa, from the corresponding amines and carbon dioxide with catalysis by triphenylstibine oxide and assistance from tetraphosphorus decasulfide (Ph3SbO/P4S10).Monitoring of the reaction by 13C NMR revealed that the successive thiolation of carbamic acid to an intermediate antimony carbamate species and aminolysis of the carbamothioic acid thus formed constitute the reaction course.Cyclic ureas can also be synthesized by similar carbonylations of diamines (RNHCH2CH2NHR'; where R, R' = H, H; Me, H; Ph, H; HOCH2CH2, H; HOCHMeCH2, H; Me, Me).Furthermore, the Ph3SbO/P4S10 catalyst system enabled the preparation of trisubstituted ureas such as 1-butyl-3,3-diethylurea by a selective cocarbonylation of butylamine and diethylamine.
- Nomura, Ryoki,Hasegawa, Yasuhiro,Ishimoto, Mikio,Toyosaki, Takayuki,Matsuda, Haruo
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p. 7339 - 7342
(2007/10/02)
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- Gem cyclodialkylation of amines and amides
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Amines and amides are N,N-cyclodialkylated by reaction with an unstrained cyclic ether in the presence of a B-subgroup metal oxide alkylation catalyst, preferably a Group IV-B metal oxide such as titanium dioxide.
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- Synthesis and reactions of 2,3-dihydrocyclohepta[b][1,4]-thiazines and 2,3-dihydro-1H-cyclohepta[b]pyrazines
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The reaction of 2-methoxytropone with ethylenediamine gave 2-(2-aminoethyl)aminotropone and 2,2′-(1,2-ethanediamino)-bis(tropone), and the former afforded 2,3-dihydro-1H-cyclohepta[b]pyrazine (13) on heating. N-Methyl compound 14 of 13 was also obtained by the similar method. 14 was led to the dimethyl cation 18b, which gave exclusively 7-bromo compound 24 with bromine in acetic acid. 18b and 24 rearranged to 1,2,3,4-tetrahydro-1, 4-dimethylquinoxaline-6-carbaldehyde with alkali, while 13 rearranged to 1-phenylimidazolin-2-one on treatment with H2O2. The reaction of 2-chlorotropone with 2-aminoethanethiol rapidly afforded 2-(2-aminoethylthio)tropone (35a), which gradually changed to 2-[2-(2-troponyl)thioethylamino]tropone (37a) and N,N′-bis(2-troponyl)-2-aminoethanedisulfide (39a) via unstable 2-(2-mercaptoethyl)-aminotropone (38a). Hydrochloride of 35a gave, upon heating, 2, 3-dihydrocyclohepta[b] [1,4]thiazine (15), which gave N-methyl cation 40 on treatment with magic methyl. 40 gradually changed with cold alkali to the disulfide 39b, via 35b, 37b, and 38b, in a manner similar to the case of their parent compounds (35a, 37a, and 38a). Possible pathways of these reactions, especially the facile exchange of the difunctionalized side-chains, are discussed.
- Nozoe, Tetsuo,Ishikawa, Sumio,Shindo, Kimio
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p. 733 - 744
(2007/10/02)
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- sYNTHESIS OF N,N'-DISUBSTITUTED UREAS FROM CARBAMATES
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A simple synthesis of N,N'-disubstituted ureas from carbamates is described involving displacement of an alkoxy group by the magnesium salt of an amine generated in situ by treatment with ethylmagnesium bromide.
- Basha, Anwer
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p. 2525 - 2526
(2007/10/02)
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- Preparation of N-substituted imidazolidinones and N-substituted 2-thionimidazolidinones
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The invention is a process for the preparation of N-substituted imidazolidinones and N-substituted 2-thionimidazolidinones which comprises contacting an oxazolidinone with a compound containing a nitrogen directly bonded to a carbonyl or a thiocarbonyl group in the presence of a Lewis acid catalyst or the hydrate of a Lewis acid catalyst under conditions such that an N-substituted imidazolidinone or N-substituted 2-thionimidazolidinone is prepared. The compound containing a nitrogen directly bonded to a carbonyl or a thiocarbonyl group is an isocyanate or isothiocyanate or a compound wherein the nitrogen is reactive and the carbonyl or thiocarbonyl group is further bonded to a substituent by a bond which is clevable under the reaction conditions. The Lewis acid catalyst corresponds to the formula wherein M is a group IB-VIIIB, IIIA or IVA element with the proviso that M is not C or Si; X is a halogen; and n is 2, 3 or 4.
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- Alkylation of amines and amides
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The invention provides the use of a B-subgroup metal oxide alkylation catalyst in alkylating an amino or amido group-containing compound using an ether alkylation agent. Thus, amines and amides may be N,N-cyclodialkylated by reaction with an unstrained cyclic ether in the presence of a B-subgroup metal oxide alkylation catalyst, preferably a Group IV-B metal oxide such as titanium dioxide.
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- Gem cyclodialkylation of amines and amides
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Amines and amides are N,N-cyclodialkylated by reaction with an unstrained cyclic ether in the presence of a B-subgroup metal oxide alkylation catalyst, preferably a Group IV-B metal oxide such as titanium dioxide.
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- HYDROLYSE BASIQUE ET DECARBOXYLATION D'ESTERS ALLOPHANIQUES EN MILIEU MIXTE ACETONITRILE-EAU: CATALYSE BIFONCTIONNELLE PAR UNE ENTITE FORMEE ENTRE BASE ET SOLVANT
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Base catalysed hydrolysis of allophanic esters-models of carboxybiotine- in acetonitrile/water mixture, shows a sharp increase in rate constant in the range of 0.1-0.3 M in water, with a maximum which is interpreted as a balance between two desolvation terms, one concerning the nucleophile, the other the anionic transition state.Moreover, in acetonitrile/water mixtures at low water content (2.10-2 M), a fast hydrolysis (kexpca.0.5 s-1 at 20 deg C) of allophanic esters (carboxy-biotin models) is observed due to catalysis by the enolate of acetamide.This speciesalso catalyses the decarboxylation step, likely behaving as a bifunctional catalyst.
- Monnier, E.,Klaebe, A,Perie, J. J.
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p. 3067 - 3070
(2007/10/02)
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- Penicillins and processes for their preparation and use
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6-[α-(Imidazolidin-2-on-1-carbonylamido)acetamido]-penicillanic acids substituted in the 3-position of the imidazolidinone ring with phenyl or a substituted phenyl group and on the α-carbon atom of the acetamido bridge with a phenyl, thienyl, cyclohexenyl or cyclohexadienyl group, and their salts, are antibacterial agents. The compounds, of which α-(3-phenylimidazolidin-2-on-1-ylcarbonylamino)benzylpenicillin is a representative example, are prepared by acylation of the corresponding 6-(α-aminoacetamido)penicillanic acid or a derivative thereof.
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