- MCL-1 INHIBITOR MACROCYCLE COMPOUNDS FOR USE IN CLINICAL MANAGEMENT OF CONDITIONS CAUSED OR MEDIATED BY SENESCENT CELLS AND FOR TREATING CANCER
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This disclosure provides small-molecule compounds with Mcl-l inhibitory activity. Compounds provided in this disclosure promote apoptosis in senescent cells, particularly when combined with inhibitors of other Bcl family proteins. Compounds provided in this disclosure also promote apoptosis in cancer cells. Such compounds can be developed for treating senescent-related conditions, or as chemotherapeutic agents.
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Paragraph 0130
(2021/05/15)
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- SYNTHESIS OF MCL-1 INHIBITOR
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Disclosed are intermediates and methods of synthesizing Compound 1.
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Page/Page column 31-32
(2018/10/25)
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- Pyrazole functionalized n-heterocyclic carbene ruthenium compound with anticancer activity and preparation method and application thereof
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The invention discloses a pyrazole functionalized n-heterocyclic carbene ruthenium compound with anticancer activity and a preparation method and application thereof. The pyrazole functionalized n-heterocyclic carbene ruthenium compound is prepared by using 5-methyl-1-hydrogen-pyrazole ethyl formate through alkylation, reduction, chlorination, salt formation and metal exchange reaction, and the general formula of the pyrazole functionalized n-heterocyclic carbene ruthenium compound is [LRu(p-cymene)Cl](X) (L=pyrazole functionalized n-heterocyclic carbene ligand, and X is anions). In the cytotoxicity test of breast cancer cells (Bcap-37), intestinal cancer cells (LoVo), gastric cancer cells (SCG7901) and cisplatin-resistant gastric cancer cells (SCG7901-R), the n-heterocyclic carbene ruthenium compound can effectively inhibit cancer cell division and reproduction. The n-heterocyclic carbene ruthenium compound is variable in structure, convenient to synthesize, stable in performance, environmentally friendly, capable of stably existing in air for a long time, and promising in application prospect of pharmaceutical industry and fine chemical engineering industry.
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- Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity
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Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
- Bruncko, Milan,Wang, Le,Sheppard, George S.,Phillips, Darren C.,Tahir, Stephen K.,Xue, John,Erickson, Scott,Fidanze, Steve,Fry, Elizabeth,Hasvold, Lisa,Jenkins, Gary J.,Jin, Sha,Judge, Russell A.,Kovar, Peter J.,Madar, David,Nimmer, Paul,Park, Chang,Petros, Andrew M.,Rosenberg, Saul H.,Smith, Morey L.,Song, Xiaohong,Sun, Chaohong,Tao, Zhi-Fu,Wang, Xilu,Xiao, Yu,Zhang, Haichao,Tse, Chris,Leverson, Joel D.,Elmore, Steven W.,Souers, Andrew J.
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p. 2180 - 2194
(2015/03/30)
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- Synthesis and enzyme inhibitory activities of some new pyrazole-based heterocyclic compounds
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Three tridentate N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-1-hydroxy-2- aminoethane (2), N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-cyclohexylamine (3) and 2-[bis (1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino]ethan-1-ol (4) are synthesized and spectroscopically characterized togetherwith 1-hydroxymethyl-3,5-dimethylpyrazole (1). These have been tested in inhibitory activities against various hyperactive enzymes like urease, β- glucuronidase, phosphodiesterase, α-chymotrypsin, acetylcholinesterase and butyrylcholinesterase. Compounds 1, 2 and 3 were found to be selective inhibitors of urease. Compound 4 was found to be selective inhibitor of butyrylcholinesterase. The nature of the junction between pyrazoles cycles determined the activities of these tripods. While the tripods are inactive towards urease or glucuronidase, they turn to be selective towards butyrylcholinesterase.
- Harit, Tariq,Malek, Fouad,Bali, Brahim El,Khan, Ajmal,Dalvandi, Kourosh,Marasini, Bishnu P.,Noreen, Shagufta,Malik, Rizwana,Choudhary, M. Iqbal,Khan, Sadia
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p. 2772 - 2778,7
(2020/08/24)
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- Stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants
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A general strategy has been devised for the stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants thereof, which relies on late stage introduction of the heterocycle through Wittig olefination of ketone 14. Formation of the macrocycle was achieved through RCM-based ring closure and introduction of the cyclopropane moiety involved a highly selective Charette cyclopropanation of allylic alcohol 7.
- Schiess, Raphael,Gertsch, Juerg,Schweizer, W. Bernd,Altmann, Karl-Heinz
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p. 1436 - 1439
(2011/05/13)
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- Ferrocenylpyrazole as building block for the design of new redox-active macrocycles
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A new bis(ferrocenyl)appended macrocycle and two new differently sized ferrocenophanes have been prepared from ferrocenylpyrazole subunits. Their structure has been established by 'H and C NMR spectroscopy and compared with that of corresponding opened ligands. Electrochemical measurements and modeling studies confirm the strain present in ferrocenophanes. Complexation reactions with Ru(DMSO)4Cl2 do not permit to isolate stable complexes. Springer-Verlag 1996.
- Chabert-Couchouron, Nathalie,Reibel, Corine,Marzin, Claude,Tarrago, Georges
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