- N -boc deprotection and isolation method for water-soluble zwitterionic compounds
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A highly efficient TMSI-mediated deprotection and direct isolation method to obtain zwitterionic compounds from the corresponding N-Boc derivatives has been developed. This method has been demonstrated in the final deprotection/isolation of the β-lactamase inhibitor MK-7655 as a part of its manufacturing process. Further application of this process toward other zwitterionic compounds, such as dipeptides and tripeptides, has been successfully developed. Furthermore, a catalytic version of this transformation has been demonstrated in the presence of BSA or BSTFA.
- Liu, Zhijian,Yasuda, Nobuyoshi,Simeone, Michael,Reamer, Robert A.
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- Synthesis, characterization and in vitro DNA binding and cleavage studies of Cu(II)/Zn(II) dipeptide complexes
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Novel dipeptide complexes Cu(II)?Val-Pro (1), Zn(II)?Val-Pro (2), Cu(II)?Ala-Pro (3) and Zn(II)?Ala-Pro (4) were synthesized and thoroughly characterized using different spectroscopic techniques including elemental analyses, IR, NMR, ESI-MS and molar conductance measurements. The solution stability study carried out by UV-vis absorption titration over a broad range of pH proved the stability of the complexes in solution. In vitro DNA binding studies of complexes 1-4 carried out employing absorption, fluorescence, circular dichroism and viscometric studies revealed the binding of complexes to DNA via groove binding. UV-vis titrations of 1-4 with mononucleotides of interest viz., 5′-GMP and 5′-TMP were also carried out. The DNA cleavage activity of the complexes 1 and 2 were ascertained by gel electrophoresis assay which revealed that the complexes are good DNA cleavage agents and the cleavage mechanism involved a hydrolytic pathway. Furthermore, in vitro antitumor activity of complex 1 was screened against human cancer cell lines of different histological origin.
- Arjmand, Farukh,Jamsheera,Mohapatra
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- Cyclo(l-proline-l-serine) Dipeptide Suppresses Seed Borne Fungal Pathogens of Rice: Altered Cellular Membrane Integrity of Fungal Hyphae and Seed Quality Benefits
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Five proline-containing diketopiperazines (Pro-DKPs) produced by antagonistic microorganisms as secondary metabolites were selected and synthesized under laboratory conditions. Out of five synthesized Pro-DKPs, cyclo(l-Pro-l-Ser) (DKP-6) revealed the best inhibition of fungal pathogens (Fusarium verticillioides and Fusarium fujikuroi) of rice under in vitro conditions with effective doses lower than standard fungicide carbendazim. DKP-6 induced stress on the fungal cell membrane integrity, which was revealed by calcofluor white and propidium iodide assays, endorsed by ultra-microscopic details and soluble protein leakage assays. In vivo seed treatment of infested rice seeds with DKP-6 at 2000 μg/mL for 10 h of seed treatment inflicted best reduction in seed rot and seedling blight with respect to control and carbendazim. Significant enhancement in seedling quality parameters were also observed. The work presented the strong influence of cyclo(l-Pro-l-Ser) as a mycocidal seed treatment agent better than synthetic toxic fungicides for rice.
- Poonia, Baninderjit Kaur,Sidhu, Anjali,Sharma, Anju Bala
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p. 2160 - 2168
(2022/02/23)
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- A process for preparing a renin - angiotensin - aldosterone system dual inhibitor compound of intermediate
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The invention relates to an intermediate compound for preparing RAAS (renin-angiotensin-aldosterone system) dual inhibitor compounds. RAAS dual inhibitors can be used for treating diseases related to an RAAS such as high blood pressure and heart diseases.
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Paragraph 0062; 0063; 0064; 0068; 0069; 0070
(2017/04/28)
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- For renin-angiotensin-aldosterone system dual inhibitor compounds
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The invention relates to a compound for a renin-angiotensin-aldosterone system dual inhibitor, which can be used for treating and blocking diseases related to an RAS system such as hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiomegaly, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complication caused by diabetes such as nephropathy, vasculopathy, neuropathy, glaucoma, intraocular pressure elevation, atherosclerosis, restenosis after the arteries transluminal angioplasty, complication of blood vessels or cardiac surgical procedures, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complication caused by the treatment of immunosuppressor and other diseases associated to the renin-angiotensin system.
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Paragraph 0077; 0078-0080
(2016/12/01)
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- RAAS system as a dual inhibitor compounds
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The invention discloses a compound used as a dual inhibitor for RAAS (rennin angiotensin aldosterone system) and particularly relates to a compound shown in formula (I), a stereisomer thereof or a pharmaceutically acceptable salt thereof. The compound can be used for treating and blocking RAS-associated diseases such as hypertension and heart disease, can be used for preventing or treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications such as nephropathy caused by diabetes, vasculopathy, vasculopathy, glaucoma, intraocular pressure elevation, atherosis, restenosis after revascularization, complications after blood vessel or cardiac operation, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complications caused by immunosuppressor treatment as well as other known diseases associated with the rennin angiotensin aldosterone system.
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Paragraph 0051; 0052-0054
(2017/02/28)
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- Functional identification and structure determination of two novel prolidases from cog1228 in the amidohydrolase superfamily
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Two uncharacterized enzymes from the amidohydrolase superfamily belonging to cog1228 were cloned, expressed, and purified to homogeneity. The two proteins, Sgx9260c (gi|44242006) and Sgx9260b (gi|44479596), were derived from environmental DNA samples originating from the Sargasso Sea. The catalytic function and substrate profiles for Sgx9260c and Sgx9260b were determined using a comprehensive library of dipeptides and N-acyl derivative of l-amino acids. Sgx9260c catalyzes the hydrolysis of Gly-l-Pro, l-Ala-l-Pro, and N-acyl derivatives of l-Pro. The best substrate identified to date is N-acetyl-l-Pro with a value of kcat/Km of 3 × 105 M -1 s-1. Sgx9260b catalyzes the hydrolysis of l-hydrophobic l-Pro dipeptides and N-acyl derivatives of l-Pro. The best substrate identified to date is N-propionyl-l-Pro with a value of kcat/Km of 1 × 105 M-1 s-1. Three-dimensional structures of both proteins were determined by X-ray diffraction methods (PDB codes 3MKV and 3FEQ). These proteins fold as distorted (β/α) 8-barrels with two divalent cations in the active site. The structure of Sgx9260c was also determined as a complex with the N-methylphosphonate derivative of l-Pro (PDB code 3N2C). In this structure the phosphonate moiety bridges the binuclear metal center, and one oxygen atom interacts with His-140. The α-carboxylate of the inhibitor interacts with Tyr-231. The proline side chain occupies a small substrate binding cavity formed by residues contributed from the loop that follows β-strand 7 within the (β/α)8-barrel. A total of 38 other proteins from cog1228 are predicted to have the same substrate profile based on conservation of the substrate binding residues. The structure of an evolutionarily related protein, Cc2672 from Caulobacter crecentus, was determined as a complex with the N-methylphosphonate derivative of l-arginine (PDB code 3MTW).
- Xiang, Dao Feng,Patskovsky, Yury,Xu, Chengfu,Fedorov, Alexander A.,Fedorov, Elena V.,Sisco, Abby A.,Sauder, J. Michael,Burley, Stephen K.,Almo, Steven C.,Raushel, Frank M.
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experimental part
p. 6791 - 6803
(2011/05/05)
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- BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres
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A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.
- Coburn, Craig A.,Stachel, Shawn J.,Jones, Kristen G.,Steele, Thomas G.,Rush, Diane M.,DiMuzio, Jillian,Pietrak, Beth L.,Lai, Ming-Tain,Huang, Qian,Lineberger, Janet,Jin, Lixia,Munshi, Sanjeev,Katharine Holloway,Espeseth, Amy,Simon, Adam,Hazuda, Daria,Graham, Samuel L.,Vacca, Joseph P.
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p. 3635 - 3638
(2007/10/03)
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- Process for the stereoselective preparation of l-alanyl-l-proline
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L-alanyl-L-proline is stereoselectively prepared catalytically hydrogenating an N-(2-iminopropionyl)-L-proline in the presence of a metal hydrogenolysis catalyst and at a pH of less than about 4. Also disclosed are improved processes for production of N-pyruvyl-L-proline in which L-proline and a 2,2-disubstituted propionyl halide are allowed to react at a pH of at least 9 to produce an L-proline intermediate which is hydrolyzed at a pH range of from about 6.5 to about 8.5 to yield N-pyruvyl-L-proline.
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- Process for the stereoselective preparation of L-alanyl-L-proline
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L-Alanyl-L-proline is stereoselectively prepared catalytically hydrogenating an N-(2-iminopropionyl)-L-proline in the presence of a metal hydrogenolysis catalyst and at a pH of less than about 4. Also disclosed are improved processes for production of pyruvylproline in which L-proline and a 2,2-disubstituted propionyl halide are allowed to react at a pH of at least 9 to produce an L-proline intermediate which is hydrolyzed at a pH range of from about 6.5 to about 8.5 to yield N-pyruvyl-L-proline.
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- Dipeptide derivatives and antihypertensive drugs containing them
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There are disclosed dipeptide derivatives represented by the general formula: STR1 wherein R1 is a radical selected from the group consisting of alkyl, aralkyl and aryl groups optionally containing one or more substituent groups, R2 is a radical selected from the group consisting of hydrogen atoms and alkyl, aralkyl and aryl groups optionally containing one or more substituent groups, R3 is a radical selected from the group consisting of hydrogen atoms and alkyl, aralkyl and aryl groups optionally containing one or more substituent groups, R4 is a radical selected from the group consisting of hydrogen atoms and alkyl, aralkyl and aryl groups optionally containing one or more substituent groups, and R5 is a radical selected from the group consisting of hydroxyl, amino, hydroxyamino, alkyloxy, aralkyloxy, aryloxy, alkylamino, aralkylamino, arylamino, alkyloxyamino, aralkyloxyamino, aryloxyamino, acylamino and sulfonylamino groups, which alkyloxy, aralkyloxy and aryloxy groups optionally containing one or more substituent groups; wherein R3 may be combined with R2 or R4 to form an alkylene bridge optionally containing one or more oxygen atoms, sulfur atoms and nitrogen atoms and optionally containing one or more substituent groups. However, certain dipeptide derivatives within the above general formula are excluded from the invention. The dipeptide derivatives are useful for the treatment of hypertension.
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- N(α)-(diphenoxyphosphoryl)-L-alanyl-L-proline, N(α)-[bis(4-nitrophenoxy)phosphoryl]-L-alanyl-L-proline, and N(α)-[2-phenylethyl)phenoxyphosphoryl]-L-alanyl-L-proline: Releasers of potent inhibitors of angiotensin converting enzyme at physiological pH and temperature
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The rate of loss of phenol or 4-nitrophenol from N(α)-(diphenoxyphosphoryl)-L-proline (2), N(α)-[bis(4-nitrophenoxy)phosphoryl]-L-alanyl-L-proline (5), and N(α)-[(2-phenylethyl-phenoxyphosphoryl]-L-analyl-L-proline (12) was determined spectrophotometrically at pH 7.5 and 37° C in both Tris and phosphate buffers. These moderately potent inhibitors of angiotensin converting enzyme (K(i) > 0.8 μM) all hydrolyze, losing 1 mol of phenol to yield highly potent inhibitors (K(i) = 0.5-18 nM). The half-times for loss of 1 mol of phenol in Tris buffer are 22 days (2), 3.4 h (5), and 21 days (12). The half-times in phosphate buffer were not significantly different. The mono(4-nitrophenoxy) ester (K(i) = 18 nM) loses its 1 mol of nitrophenol with a half-time of 35 h to yield N(α)-phosphoryl-L-alanyl-L-proline (K(i) = 1.4 nM), which hydrolyzes at the P-N bond with a half-time of 2.2 h. Hydrolysis of the P-N bond in 2 and 12 was not observed during the time course of the kinetic experiments. The two phosphoramidate diesters 2 and 5 and the phosphonamidate monoester 12 thus release powerful inhibitors of angiotensin converting enzyme with a known time course at physiological pH and temperature in vitro. A time-dependent increase in inhibitory potency against converting enzyme that paralleled the kinetics of phenyl ester hydrolysis was confirmed in vitro.
- Galardy,Grobelny
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p. 1422 - 1427
(2007/10/02)
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- PHOSPHONAMIDATE COMPOUNDS
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Phosphonamidates of the formula STR1 wherein X is a substituted or unsubstituted imino or amino acid or ester. These compounds possess angiotensin converting enzyme activity and are thus useful as hypotensive agents.
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