- Catalyst Repurposing Sequential Catalysis by Harnessing Regenerated Prolinamide Organocatalysts as Transfer Hydrogenation Ligands
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A catalyst repurposing strategy based on a sequential aldol addition and transfer hydrogenation giving access to enantiomerically enriched α-hydroxy-γ-butyrolactones is described. The combination of a stereoselective, organocatalytic step, followed by an efficient catalytic aldehyde reduction induces an ensuing lactonization to provide enantioenriched butyrolactones from readily available starting materials. By capitalizing from the capacity of prolineamides to act as both an organocatalyst and a transfer hydrogenation ligand, catalyst repurposing allowed the development of an operationally simple, economic, and efficient sequential catalysis approach.
- Bourgeois, Frederic,Medlock, Jonathan A.,Bonrath, Werner,Sparr, Christof
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supporting information
p. 110 - 115
(2019/12/30)
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- Macrocyclic MCL-1 inhibitors and methods of use
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The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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- INHIBITORS OF PLASMA KALLIKREIN AND USES THEREOF
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Provided herein are compounds that inhibit pKal, a serine protease whose activity is responsible for proteolytically cleaving kininogen and generating the potent vasodilator and pro-inflammatory peptide bradykinin, which can lead to painful and debilitating inflammatory attacks (e.g., edema). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating pKal-related diseases and disorders (e.g., edema) with the compounds in a subject, by administering the compounds and/or compositions described herein.
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Paragraph 00319; 00320; 00337
(2019/02/17)
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- MACROCYCLIC MCL-1 INHIBITORS AND METHODS OF USE
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The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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Paragraph 00425
(2019/03/05)
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- Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed α-Hydrazination
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An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented. The tetramethyltryptophan moiety is assembled by tert-prenylation of indole, followed by the high-yielding organocatalyzed α-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. 2-Bromo-N-ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling completes the synthesis, being the first approach that does not employ chiral auxiliaries. A novel phenonium-type rearrangement of the indole system occurred when subjecting dihydroxylated 3-tert-prenylindole to Mitsunobu conditions.
- Lang, Jan Hendrik,Jones, Peter G.,Lindel, Thomas
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supporting information
p. 12714 - 12717
(2017/09/25)
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- OXADIAZOLE COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The invention provides novel beta-secretase inhibitors and methods for their including methods of treating Alzheimer's disease.
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Page/Page column 91
(2012/05/05)
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- COMPOUNDS CONTAINING FUSED RINGS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimer's disease.
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Page/Page column 83-84
(2011/11/01)
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- Novel pyrrolidine heterocycles as CCR1 antagonists
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A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptab
- Merritt, J. Robert,James, Ray,Paradkar, Vidyadhar M.,Zhang, Chongwu,Liu, Ruiyan,Liu, Jinqi,Jacob, Biji,Chiriac, Camelia,Ohlmeyer, Michael J.,Quadros, Elizabeth,Wines, Pamela,Postelnek, Jennifer,Hicks, Catherine M.,Chen, Weiqing,Kimble, Earl F.,O'Brien, Linda,White, Nicole,Desai, Hema,Appell, Kenneth C.,Webb, Maria L.
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supporting information; experimental part
p. 5477 - 5479
(2010/12/24)
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- Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)
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A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.
- Diakos, Connie I.,Zhang, Mei,Beale, Philip J.,Fenton, Ronald R.,Hambley, Trevor W.
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experimental part
p. 2807 - 2814
(2009/10/10)
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- ORTHO PYRROLIDINE, BENZYL-SUBSTITUTED HETEROCYCLE CCR1 ANTAGONISTS FOR AUTOIMMUNE DISEASES and INFLAMMATION
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Compounds of the formula are disclosed. The compounds are CCR1 antagonists which are useful for the treatment and prevention of inflammatory and autoimmune diseases. Other embodiments are also disclosed.
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Page/Page column 29-30
(2009/04/24)
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- Organocatalysis with proline derivatives: Improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions
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Tetrazole and acylsulfonamide organocatalysts derived from proline have been synthesised and applied to the asymmetric Mannich, nitro-Michael and aldol reactions to give results that are superior to the proline-catalysed counterpart.
- Cobb, Alexander J. A.,Shaw, David M.,Longbottom, Deborah A.,Gold, Johan B.,Ley, Steven V.
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- Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato) platinum(II)
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The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.
- Morikawa,Honda,Endoh -i.,Matsumoto,Akamatsu -i.,Mitsui,Koizumi
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p. 837 - 842
(2007/10/02)
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