15159-65-6Relevant articles and documents
Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents
Almaliti, Jehad,Miller, Bailey,Pietraszkiewicz, Halina,Glukhov, Evgenia,Naman, C. Benjamin,Kline, Toni,Hanson, Jeffrey,Li, Xiaofan,Zhou, Sihong,Valeriote, Frederick A.,Gerwick, William H.
, p. 416 - 432 (2018/10/31)
Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.
Enantiopure azetidine-2-carboxamides as organocatalysts for direct asymmetric aldol reactions in aqueous and organic media
Song, Xixi,Liu, Ai-Xiang,Liu, Shan-Shan,Gao, Wen-Chao,Wang, Min-Can,Chang, Junbiao
, p. 1464 - 1470 (2014/02/14)
A family of enantiopure azetidine-2-caboxamides was asymmetrically synthesized, and was examined as organocatalyst in direct aldol reactions. A well chosen chiral azetidine-2-caboxamide was found to smoothly catalyze the direct aldol reaction of various benzaldehydes with acetone in brine, and β-hydroxy ketones were produced with enantiomeric excess up to 96%. The reaction of benzaldehydes with cyclic ketones also led to the formation of anti-products in diastereomeric ratio up to 99:1 and enantiomeric excess up to 99%.
Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease
Jiang, Yutong,Andrews, Steven W.,Condroski, Kevin R.,Buckman, Brad,Serebryany, Vlad,Wenglowsky, Steve,Kennedy, April L.,Madduru, Machender R.,Wang, Bin,Lyon, Michael,Doherty, George A.,Woodard, Benjamin T.,Lemieux, Christine,Do, Mary Geck,Zhang, Hailong,Ballard, Joshua,Vigers, Guy,Brandhuber, Barbra J.,Stengel, Peter,Josey, John A.,Beigelman, Leonid,Blatt, Lawrence,Seiwert, Scott D.
supporting information, p. 1753 - 1769 (2014/04/03)
HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate im