- MALT1 INHIBITORS AND USES THEREOF
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Provided herein are compounds of Formula (I) and pharmaceutical compositions thereof, which may be useful as MALT1 inhibitors. Also provided are for the treatment of proliferative disorders (e.g., cancer (e.g., non-Hodgkin' s lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis,an autoimmune disease, an inflammatory disease, an autoinflammatory disease) by administering a compound of Formula (I).
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Paragraph 00327; 00334
(2019/08/15)
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- Total synthesis of wewakazole B
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Wewakazole B is a novel cyclodecapeptide with highly potent cytotoxic activity isolated from a sample of M. producens collected from the Red Sea. It contains nine common and three modified amino acid residues. The first total synthesis of Wewakazole B was successfully achieved on a gram scale, unambiguously confirming its structure. Notable features include the careful choice of amino acid-protecting groups and the construction of three different substituted oxazoles present in this natural product.
- Long, Bohua,Zhang, Jingzhao,Tang, Xudong,Wu, Zhengzhi
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supporting information
p. 9712 - 9715
(2016/10/31)
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- A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline
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A procedure for the cyclization of dipeptidoyl benzotriazolides containing proline derivatives promoted by triethylamine under MW activation is introduced. The reaction is general for a variety of dipeptidoyl benzotriazolides and represents a very practical and convenient method for the preparation of Pro- or Hyp-derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with a disulfide linker. This method can be used for the construction of 2,5-DKP compound libraries and for the synthesis of natural products with diketopiperazine cores. This journal is
- Nsengiyumva, Olivier,Hamedzadeh, Sadra,McDaniel, James,Macho, Jocelyn,Simpson, Grant,Panda, Siva S.,Ha, Khanh,Lebedyeva, Iryna,Faidallah, Hassan M.,Al-Mohammadi, Manal Metgen,Hall, C. Dennis,Katritzky, Alan R.
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p. 4399 - 4403
(2015/04/14)
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- A new benzotriazole-mediated stereoflexible gateway to hetero-2,5- diketopiperazines
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Open chain Cbz-L-aa1-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5- diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results. Stereoflexible route to DKPs: A convenient, versatile, and flexible benzotriazole-mediated methodology for the synthesis of proline-containing hetero-2,5-diketopiperazines (DKPs) is reported. Depending on the reaction conditions, either cis- or trans-configured DKPs were obtained starting from the same inexpensive l,l-dipeptidoyl benzotriazole key intermediate (see scheme). Kinetics, chiral HPLC, and computational studies forged a background for mechanistic rationalization. Copyright
- Monbaliu, Jean-Christophe M.,Hansen, Finn K.,Beagle, Lucas K.,Panzner, Matthew J.,Steel, Peter J.,Todadze, Ekaterina,Stevens, Christian V.,Katritzky, Alan R.
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supporting information; experimental part
p. 2632 - 2638
(2012/04/17)
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- Efficient peptide coupling involving sterically hindered amino acids
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(Chemical Equation Presented) Hindered amino acids have been introduced into peptide chains by coupling N-(Cbz- and Fmoc-α-aminoacyl) benzotriazoles with amino acids, wherein at least one of the components was sterically hindered, to provide compounds 3a-e, (3c +3 c′), 5a-d, (5a + 5a′), 6a-c, (6b + 6b′), 8a-c, 9a-e, 10a-d, and (10a + 10a′) in isolated yields of 41-95% with complete retention of chirality as evidenced by NMR and HPLC analysis. The benzotriazole activation methodology is a new route for the synthesis of sterically hindered peptides. (Note: compound numbers written within brackets represent diastereomeric mixtures or racemates; compound numbers without brackets represent enantiomers.)
- Katritzky, Alan R.,Todadze, Ekaterina,Angrish, Parul,Draghici, Bogdan
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p. 5794 - 5801
(2008/02/09)
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- Microwave irradiated high-speed solution synthesis of peptide acids employing Fmoc-amino acid pentafluorophenyl esters as coupling agents
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A high-speed solution phase synthesis of peptide acids employing commercially available Fmoc-amino acid pentafluorophenyl esters as coupling agents has been demonstrated. The coupling has been found to be fast and completed in 30-45 sec. A simple work-up of the reaction mixture has resulted N-protected peptide acids in good yield. Utilizing the present method, the coupling of difficult sequences containing highly hindered α, α-dialkyl amino acids has also been demonstrated. Further, the synthesis of diastereomeric dipeptides, Fmoc-Phg-Phe-OMe and Fmoc-D-Phg-Phe-OMe revealed that the coupling is free from racemization.
- Suresh Babu, Vommina V.,Ramana Rao
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p. 2328 - 2332
(2007/10/03)
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- Influence of solvent viscosity on the rate of hydrolysis of dipeptides by carboxypeptidase Y
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The influence of solvent viscosity on the rate of enzymatic hydrolysis of a series of dipeptides (Z-Phe-Gly, Z-Phe-Sar, Z-Phe-Ala, Z-Phe-NMeAla, Z-Phe-Aib and Z-Phe-Pro) by carboxypeptidase Y was investigated. The effect of solvent viscosity on the enzymatic hydrolysis revealed that whereas all Kcat values decreased with viscosity, those of the N-alkyl peptides decreased more than those of the N-H peptides. The kinetic behaviour implies the involvement of conformational changes of the enzyme in terms of the 'induced-fit' process. Copyright
- Kanosue, Yoshifumi,Kojima, Satoshi,Ohkata, Katsuo
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p. 448 - 457
(2007/10/03)
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- Relationship between the hydrophobicity of dipeptides and the Michaelis-Menten constant Km of their hydrolysis by carboxypeptidase-Y and carboxypeptidase-A
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The enzymatic hydrolysis of dipeptides by carboxypeptidase-Y and carboxypeptidase-A was investigated. In the enzymatic hydrolysis of the dipeptides, a good linear relationship (r = 0.997 and 0.999) was found between the Michaelis-Menten constant (Km) and the hydrophobicity of the substrates evaluated from relative elution volume in reversed-phase HPLC. The correlation suggests that the hydrophobicity of the C-terminal amino acid is a major factor in governing the stability of the enzyme-substrate complex. The difference in the slope of the linear-regression lines seems to reflect the degree of relative hydrophobicity of the binding pockets in carboxypeptidase-Y and carboxypeptidase-A.
- Kanosue, Yoshifumi,Kojima, Satoshi,Hiraga, Yoshikazu,Ohkata, Katsuo
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p. 1187 - 1193
(2007/10/03)
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- Total synthesis and assignment of configuration of lissoclinamide 7
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The first total synthesis of lissoclinamide 7, a 21-membered cyclopeptide isolated from Lissoclinum bistratum, was accomplished in 23 steps and 4.4% overall yield. The extraordinary configurational lability of the thiazoline segments was overcome by a novel strategy combining the use of the Burgess reagent for multiple simultaneous oxazoline and thiazoline formations and an efficient oxazoline → thiazoline heterocycle interconversion. In addition to the total synthesis, this work highlights the scope of alternative strategies toward Lissoclinum peptides and presents the preparation of analogues for SAR studies of the cytotoxic effects of this family of marine natural products.
- Wipf, Peter,Fritch, Paul C.
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p. 12358 - 12367
(2007/10/03)
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- HETEROCYCLIC THROMBIN INHIBITORS
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Heterocyclic thrombin inhibitors are provided which have the structure STR1 wherein n, R, R 1, R 2, R 3, G, G x, R. sup.6', Ra, Xa, R 6, Rb, R 3, p, Q, A and R 4 are as defined herein.
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- Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin
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Z-D-Phe-Pro-boroMpg-OPin (9a) has been shown previously to be a highly specific inhibitor of thrombin in spite of lacking an arginine-like guanidino group at the P1 site. A range of compounds have been synthesized based upon this lead compound, varying the neutral side chain at the P1 site. Of the 20 examples based upon the structures at P2 and P3 of Z-D-X-Pro (X being Phe or β,β-diphenylalanine), all were found to be effective inhibitors of thrombin (K(i)'s between 10 and 100 nM). Furthermore all exhibited a high specificity toward thrombin having values for aK(i)(trypsin)/K(i)(thrombin) ratio of between 10- and 100-fold. High ratio values were found for a number of the compounds tested against a range of serine proteinases (plasmin, factor Xa, kallikrein, urokinase, protein Ca, chymotrypsin, elastase, and cathepsin G). As far as potency toward thrombin, compounds containing the methoxypropyl group at P1 were favored over those with a methoxy grouping on a shorter alkyl chain (8) or without the methoxy group (1-5). The compounds display potent anticoagulant activity with values for 18 in thrombin time of 0.63 μM and in activated partial thromboplastin time of 2.0 μM. 11B NMR has been used to confirm interaction of the boron atom with the active site. From the high specificity shown with all the compounds we propose that the compounds, constitute a new class of thrombin inhibitors.
- Deadman,Elgendy,Goodwin,Green,Baban,Patel,Skordalakes,Chino,Claeson,Kakkar,Scully
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p. 1511 - 1522
(2007/10/02)
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- SYNTHESIS AND BIOLOGICAL ACTIVITIES OF NEW ANALOGUES OF β-CASOMORPHINE-5*
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Four new analogues of β-casomorphine-5 modified at the C-end by modifiers based on ethylenediamine and glycine residues have been synthesized. the opioid and analgesic activities of the peptides obtained comparison with β-casomorphine-5 and morphine are discussed.
- Sobirov, M.M.,Khalikov, Sh.Kh.,Saidov, S.S.,Kodirov, M.Z.,Zaitsev, S.V.,et al.
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p. 397 - 405
(2007/10/02)
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- A One-Pot Peptide Synthesis via Se-phenyl Carboselenoate in Mixed Aqueous/Organic Solvent System
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A one pot synthesis of peptides with free C-terminal residues has been accomplished via the active Se-phenyl carboselenoate using diphenyl diselenide, tributylphosphine, and N-methylmorpholine N-oxide in an acetonitrile- water mixed solvent system.Free amino acids and peptides have been used as the amine component without pH adjustment.
- Ghosh, Sunil Kumar,Singh, Usha,Chandha, Mohindra S.,Mamdapur, Vasant R.
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p. 1566 - 1568
(2007/10/02)
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- Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation, and its stable N-methyl derivative, D-MePhe-Pro-Arg-H
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D-Phe-Pro-Arg-H sulfate (GYKI-14166) is a highly active and selective inhibitor of thrombin both in vitro and in vivo. Recent studies on the stability of D-Phe-Pro-Arg-H in neutral aqueous solution at higher temperature have revealed that it is transformed into inactive 5,6,8,9,10,10a-hexahydro-2-(3'-guanidinopropyl)-5-benzyl-6-oxo-imidazo [1,2-a]pyrrolo[2,1-c]pyrazine. No such inactivation could be observed with Boc-D-Phe-Pro-Arg-H (GYKI-14451), but this compound was far less specific than the free peptide as it inhibited thrombin and, for instance, plasmin equally well. Assuming that the transformation of free tripeptide aldehyde, mentioned above, can only be initiated by a primary amino terminus, the N-alkyl derivatives of D-Phe-Pro-Arg-H were prepared. Of the new analogues, D-MePhe-Pro-Arg-H (GYKI-14766) proved to be as highly active and selective anticoagulant as its parent compound and was not inactivated by transformation into a heterocyclic compound.
- Bajusz,Szell,Bagdy,Barabas,Horvath,Dioszegi,Fittler,Szabo,Juhasz,Tomori,Szilagyi
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p. 1729 - 1735
(2007/10/02)
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- SYNTHESIS OF A HEPTAPEPTIDE FORMING A MODIFIED ACTH 4-10 FRAGMENT
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A scheme is given for the synthesis of a heptapeptide representing a modified ACTH 4-10 fragment on the basis of which it is possible to create a preparation that is an effective adaptogen of peptide nature.A proposed variant of the synthesis permits a peptide with an adequate degree of purity to be obtained comparatively simply on a large scale.The intermediate compunds and the final products were obtained with good yields and were distinguished by chromatographic homogeneity.The heptapeptide synthesized did not differ with respect to its physicochemical characteristics and biological action from the analogous compound obtained previously.Some physicochemical characteristics of the compound obtained (angles of optical rotation, chromatographic mobilities) are given.
- Krysin, E. P.,Karel'skii, V. N.,Rabinovich, A. K.,Borovkova, S. Yu.
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p. 706 - 709
(2007/10/02)
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