Low catalyst loadings in olefin metathesis: Synthesis of nitrogen heterocycles by ring-closing metathesis
(Chemical Equetion Presentation) A series of ruthenium catalysts have been screened under ring-closing metathesis (RCM) conditions to produce five-, six-, and seven-membered carbamate-protected cyclic amines. Many of these catalysts demonstrated excellent RCM activity and yields with as low as 500 ppm catalyst loadings. RCM of the five-membered carbamate series could be run neat, the six-membered carbamate series could be run at 1.0 M, and the seven-membered carbamate series worked best at 0.2-0.05 M.
Kuhn, Kevin M.,Champagne, Timothy M.,Hong, Soon Hyeok,Wei, Wen-Hao,Nickel, Andrew,Lee, Choon Woo,Virgil, Scott C.,Grubbs, Robert H.,Pederson, Richard L.
Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma
Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.
Wang, Xiaojing,Blackaby, Wesley,Allen, Vivienne,Chan, Grace Ka Yan,Chang, Jae H.,Chiang, Po-Chang,Diène, Coura,Drummond, Jason,Do, Steven,Fan, Eric,Harstad, Eric B.,Hodges, Alastair,Hu, Huiyong,Jia, Wei,Kofie, William,Kolesnikov, Aleksandr,Lyssikatos, Joseph P.,Ly, Justin,Matteucci, Mizio,Moffat, John G.,Munugalavadla, Veerendra,Murray, Jeremy,Nash, David,Noland, Cameron L.,Del Rosario, Geoff,Ross, Leanne,Rouse, Craig,Sharpe, Andrew,Slaga, Dionysos,Sun, Minghua,Tsui, Vickie,Wallweber, Heidi,Yu, Shang-Fan,Ebens, Allen J.
(2019/03/07)
Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase
5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.
Longshaw, Alistair I.,Adanitsch, Florian,Gutierrez, Jemy A.,Evans, Gary B.,Tyler, Peter C.,Schramm, Vern L.
experimental part
p. 6730 - 6746
(2010/12/24)
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