- Immunoproteasome Inhibitor-Doxorubicin Conjugates Target Multiple Myeloma Cells and Release Doxorubicin upon Low-Dose Photon Irradiation
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Proteasome inhibitors are established therapeutic agents for the treatment of hematological cancers, as are anthracyclines such as doxorubicin. We here present a new drug targeting approach that combines both drug classes into a single molecule. Doxorubicin was conjugated to an immunoproteasome-selective inhibitor via light-cleavable linkers, yielding peptide epoxyketone-doxorubicin prodrugs that remained selective and active toward immunoproteasomes. Upon cellular uptake and immunoproteasome inhibition, doxorubicin is released from the immunoproteasome inhibitor through photoirradiation. Multiple myeloma cells in this way take a double hit: immunoproteasome inhibition and doxorubicin-induced toxicity. Our strategy, which entails targeting of a cytotoxic agent, through a covalent enzyme inhibitor that is detrimental to tumor tissue in its own right, may find use in the search for improved anticancer drugs.
- Dekker, Patrick M.,Florea, Bogdan I.,Maiorana, Santina,Maurits, Elmer,Neefjes, Jacques J. C.,Overkleeft, Herman S.,Van De Graaff, Michel J.,Van Der Zanden, Sabina Y.,Van Kasteren, Sander I.,Wander, Dennis P. A.
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p. 7250 - 7253
(2020/08/06)
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- Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes
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Air-stable Rh complexes ligated by strongly σ-donating cyclic (amino)(alkyl)carbenes (CAACs) show unique catalytic activity for the selective hydrogenation of aromatic ketones and phenols by reducing the aryl groups. The use of CAAC ligands is essential for achieving high selectivity and conversion. This method is characterized by its good compatibility with unsaturated ketones, esters, carboxylic acids, amides, and amino acids and is scalable without detriment to its efficiency.
- Wei, Yu,Rao, Bin,Cong, Xuefeng,Zeng, Xiaoming
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supporting information
p. 9250 - 9253
(2015/08/11)
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- DIAMINOPROPANOL RENIN INHIBITORS
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Described are diaminopropanols of which are orally active and bind to renin to inhibit its activity. They are useful in the treatment or amelioration of diseases associated with elevated levels of renin activity or in the treatment of aspartic protease me
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- Pyrrolidine derivatives
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The invention relates to novel pyrrolidine derivatives represented by formula (1): STR1 wherein: R1 represents (1) a lower alkyl group having 1 to 6 carbon atoms, or (2) a 3- to 15-membered mono- or fused cyclic hydrocarbon group which may contain a hetero atom on the ring, or which may be substituted with a substituent(s); each of n and m represents an integer and the sum of n and m is an integer of 0 to 2; each of X and E represents oxygen, NR' (wherein R' is hydrogen or a lower alkyl group having 1 to 6 carbon atoms), sulfur, phenylene, CH=CH or CH2 ; A represents an amino acid residue or an imino acid residue, which functional group may be optionally protected, or a glycine residue which may be substituted at the amino moiety thereof; and, Y1 represents a cycloalkyl group having 3 to 8 carbon atoms; or a salt thereof. The pyrrolidine derivatives inhibit a prolyl endopeptidase and are expected to be effective for the treatment of amnesia.
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- Poststatin, a new inhibitor of prolyl endopeptidase. VII. N-cycloalkylamide analogues
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Poststatin analogues containing (S)-2-oxo-2-(2-pyrrolidinyl)acetyl moiety in P1 were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Introduction of non-peptidyl cycloalkylamine component in P'1 was effective and P3-acyl groups must be widely modifiable for prolyl endopeptidase inhibition. Acyl-L-phenylalanyl-(S)-2-oxo-2-(2-pyrrolidinyl)acetyl-cycloalkylamide type compounds showed IC50 value of nano to subnano g/ml as prolyl endopeptidase inhibitor and were shown no significant inhibitory activities against cathepsin B, a cysteine protease.
- Tsuda, Makoto,Muraoka, Yasuhiko,Nagai, Machiko,Aoyagi, Takaaki,Takeuchi, Tomio
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p. 909 - 920
(2007/10/03)
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- THE SYNTHESIS OF HETEROCYCLIC C-TERMINAL UNITS WHICH MIMIC THE TRANSITION STATE IN THE CLEAVAGE OF THE LEU-VAL BOND OF ANGIOTENSINOGEN BY RENIN
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The stereospecific synthesis of (S)2-amino-3-cyclohexyl-(R)1-(2-furanyl)-propan-1-ol (17) and (S)2-amino-3-cyclohexyl-(R)1-(2-thienyl)-propan-1-ol (18) from t-Boc-L-phenylalanine is described.Reduction of the furan ring of (4S-trans)-4-(cyclohexylmethyl)-
- Albright, J. Donald,Howell, Charles F.,Sum, F. W.
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p. 737 - 754
(2007/10/02)
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- LARGE-SCALE SYNTHESIS OF ANTICOAGULANT DECAPEPTIDE MDL 28050
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A solution phase synthesis of the anticoagulant decapeptide Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-D-Glu-OH ( 1, MDL 28050) on a large scale is decribed.Our strategy employed in the 24-step total synthesis relies on a convergent approach.The basic feature is the preparation and the coupling of two protected pentapeptides, 2 and 3.Several key intermediates were purified by crystallizations including the protected decapeptide 21.Only a single purification required preparative HPLC.Using this synthetic route, we prepared 98percent pure final product on a 40-g scale.The overall yield of this process is about 20percent.
- Hoekstra, William J.,Sunder, Shyam S.,Cregge, Robert J.,Ashton, Louis A.,Stewart, Kenneth T.,King, Chi-Hsin R.
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p. 307 - 318
(2007/10/02)
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- Synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide
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A stereoselective synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid-n-butyl amide from Boc-L-phenylalanine is described.
- Poss,Reid
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p. 1411 - 1414
(2007/10/02)
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- DIOL SULFONAMIDE AND SULFINYL RENIN INHIBITORS
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Compounds of the formula STR1 wherein Z is SO or SO 2 possess renin inhibition activity and are useful in treating hypertension and other diseases where the reduction of the levels of circulating angiotensin II are beneficial.
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- N-HETEROCYCLIC ALCOHOL DERIVATIVES
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Compounds of the formula STR1 wherein R 1 is an N-heterocyclic group as defined herein and Y can be--NH--,--O--or--CH. sub.2--, are disclosed. These compounds are inhibitors of renin and therefore useful as cardiovascular agents.
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- Novel amino acid derivatives possessing renin-inhibitory activities
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An amino acid derivative of the general formula: wherein, R1? is a lower alkyl group and R11 is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R1? and R11 are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+ 1-O-CO-(n is as defined above) or R13 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H?C)n-O-, R12-NH-(n and R12 are as defined above) and pyridyl group; X is-CH?-,-O-or-NH-and Y is-O-or-NH-; wherein (wherein Z is-O-,-S-,-S(O)-,-S(O)?-,-CH?-,-CH(OH)-,---,-NH-or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R? is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.
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- Enkephalin analogs
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The invention relates to novel enkephalin analogs of the formula: STR1 which are useful as analgesic agents.
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- Enkephalin analogs
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The invention relates to novel enkephalin analogs of the formula: STR1 which are useful as analgesic agents.
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