- Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates
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Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
- Staben, Leanna R.,Chen, Jinhua,Cruz-Chuh, Josefa dela,Del Rosario, Geoff,Go, Mary Ann,Guo, Jun,Khojasteh, S. Cyrus,Kozak, Katherine R.,Li, Guangmin,Ng, Carl,Lewis Phillips, Gail D.,Pillow, Thomas H.,Rowntree, Rebecca K.,Wai, John,Wei, BinQing,Xu, Keyang,Xu, Zijin,Yu, Shang-Fan,Zhang, Donglu,Dragovich, Peter S.
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p. 9603 - 9622
(2020/10/19)
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- Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis
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Chiral nitriles are valuable molecules in modern organic synthesis and drug discovery. Selectively differentiating the two nitrile groups of widely available malononitrile derivatives is a straightforward yet underdeveloped route to construct enantioenriched nitriles. Here we report an enantioselective nickel-catalyzed desymmetrization of malononitriles for the generation of nitrile-containing all-carbon quaternary stereocenters. This protocol involves a nickel-catalyzed addition of aryl boronic acids to alkynes, followed by a selective nitrile insertion, providing unprecedented access to enantioenriched 5-7-membered α-cyano-cycloenones with a fully substituted olefin from a broad range of substrates. The synthetic utility of these nitrile products is demonstrated by gram-scale synthesis and conversion to several useful functional groups.
- Lu, Zhiwu,Hu, Xu-Dong,Zhang, Hui,Zhang, Xiao-Wen,Cai, Jinhui,Usman, Muhammad,Cong, Hengjiang,Liu, Wen-Bo
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supporting information
p. 7328 - 7333
(2020/08/19)
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- Asymmetric synthesis of 12-hydroxyheptadecatrienoic acid and its 5,6-dihydro- and 14,15-dehydro-derivatives
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Natural 12-hydroxyheptadecatrienoic acid (12-HHT) with an S configuration was synthesised by a Suzuki-Miyaura coupling of C10-C17 iodo alcohol with C1-C9 vinylborane. The iodo alcohol was synthesised by utilising Sharpless asymmetric epoxidation of the corresponding trimethylsilyl alcohol. The method yielded more than 100 mg of 12-HHT. Similarly, syntheses of 5,6-dihydro- and 14,15-dehydro derivatives of 12-HHT, known as HHD and HHTE, respectively, were completed in a stereoselective manner.
- Kobayashi, Yuichi,Morita, Masao,Ogawa, Narihito,Kondo, Daiki,Tojo, Toshifumi
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p. 10667 - 10673
(2016/11/30)
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- Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero-Functionalized Triazoles
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The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.
- Wang, Weiguo,Peng, Xianglong,Wei, Fang,Tung, Chen-Ho,Xu, Zhenghu
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supporting information
p. 649 - 653
(2016/02/27)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula Ia and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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Paragraph 0223
(2016/10/06)
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- RADIOLABELED ANALOG(S) OF COMPOUND 0118 AND USE THEREOF IN CONNECTION WITH PET AND/OR SPECT IMAGING TO DETERMINE WHETHER A PHARMACEUTICAL CONTAINING COMPOUND 0118 IS A CANDIDATE CANCER TREATMENT FOR A PATIENT
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A method for determining whether compound 0118 is a candidate treatment for a patient includes processing, via a processor, image data of tissue of interest of a patient including a cancer to determine whether a radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data and generating a signal indicating that compound 0118 is a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data, wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a sub-type of cancer having a galectin-1 molecular target, which is a sub-type of treatable by compound 0118.
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Page/Page column 15
(2014/01/08)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula Ia and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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Page/Page column 101
(2013/03/26)
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- Expedient construction of the [7-5-5] all-carbon tricyclic core of the daphniphyllum alkaloids daphnilongeranin B and daphniyunnine D
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A synthetic strategy for the construction of the [7-5-5] all-carbon tricyclic core of numerous calyciphylline A-type Daphniphyllum alkaloids has been developed using a key intramolecular Pauson-Khand reaction. A subsequent base-mediated double-bond migration and a regio-and stereoselective radical late stage allylic oxygenation provide access to the substitution patterns of daphnilongeranin B and daphniyunnine D.
- Darses, Benjamin,Michaelides, Iacovos N.,Sladojevich, Filippo,Ward, John W.,Rzepa, Paula R.,Dixon, Darren J.
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supporting information; experimental part
p. 1684 - 1687
(2012/06/30)
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- Total synthesis of RNA-polymerase inhibitor ripostatin B and 15-deoxyripostatin A
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Keep me skipped: A highly convergent total synthesis of ripostatin B, an inhibitor of the bacterial RNA polymerase, is described. The key steps to construct and avoid isomerization of the skipped triene are a double Stille cross-coupling reaction and a ring-closing metathesis. Furthermore, 15-deoxyripostatin A, a stable and conformationally locked analogue of ripostatin A (see scheme, 15-OH group red), was prepared and tested in vivo. Copyright
- Tang, Wufeng,Prusov, Evgeny V.
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supporting information; experimental part
p. 3401 - 3404
(2012/06/29)
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- Chemoselectivities in the platinum-catalyzed hydrative carbocyclizations of oxo-alkyne-nitrile functionalities
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Two new hydrative carbocyclizations of oxa-alkyne-nitrile functionalities are reported to produce distinct nitrogen-containing heterocycles. Protracted heating of oxoalkynyl nitrile substrates with PtCl2/CO/H2O in hot 1,4-dioxane gave 2,3-dihydro-1H-pyrido[1.2-b]-isoquinolin-4(6H)-ones. In this hydration reaction, dicarbonyl nitrile intermediates were isolated efficiently after a brief period, and they were subjected to an NHC-based crossed benzoin coupling to give spiro alcohols that further reacted with TfOH to give spiro[indene-2,2′-piperidine]-1,6′(3H)-diones.
- Mukherjee, Anupam,Liu, Rai-Shung
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supporting information; experimental part
p. 660 - 663
(2011/05/03)
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- BICYCLIC HETEROCYCLE DERIVATIVES AND USE THEREOF AS GPR119 MODULATORS
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The present invention relates to Bicyclic Heterocycle Derivatives of formula (I), compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR1 19 in a patient.
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Page/Page column 216-217
(2009/12/27)
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- Formation of seven- and eight-membered rings by Mn(III)-based oxidative free-radical cyclization
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Oxidative free-radical cyclizations of acetoacetates 1, 8, 17, and 20 with Mn(OAc)3·2H2 and Cu(OAc)2·H2O in acetic acid provide cycloheptenes and cyclooctenes in moderate to good yield. Tandem cyclizations of 28, 35 and 51 provide bicyclo[4.2.1]nonanes, bicyclo[5.2.1]decanes, bicyclo[5.3.0]decanes and bicyclo[6.3.0]undecanes.
- Snider, Barry B.,Merritt, John E.
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p. 8663 - 8678
(2007/10/02)
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- Catalytic Asymmetric C-C Bond Formation: Asymmetric Synthesis of cis-Decalin Derivatives by Palladium-Catalyzed Cyclization of Prochiral Alkenyl Iodides
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A catalytic asymmetric synthesis by the use of a Heck-type reaction has been realized for the first time, giving the cis-decalin derivative 5 in up to 46percent ee.
- Sato, Yoshihiro,Sodeoka, Mikiko,Shibasaki, Masakatsu
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p. 4738 - 4739
(2007/10/02)
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