- N8-Glycosylated 8-Azapurine and Methylated Purine Nucleobases: Synthesis and Study of Base Pairing Properties
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In this report, we present the synthesis of N8-glycosylated 8-aza-2-methylhypoxanthine and 8-aza-6-thiohypoxanthine 2′-deoxynucleosides as well as methylated 2′-deoxynebularine derivatives. In vitro base pairing properties between each modified and canonical nucleobase were studied. As demonstrated by Tm, incorporation of the modified bases in DNA resulted, with few exceptions, in low stability of duplexes. Modified bases studied in this report are preferentially recognized by T (for N8-glycosylated 8-aza-2-methylhypoxanthine and methylated purines) and G (N8-glycosylated 8-aza-2-methylhypoxanthine). The base pair formed between N8-glycosylated 8-aza-6-thiohypoxanthine and N9-glycosylated 2-methyl-6-thiohypoxanthine (X2:X6) showed, to some extent, an orthogonal interaction. Based on Tm studies, the only potential self-pairing system is formed by the N8-glycosylated 8-aza-6-thiohypoxanthine nucleoside (X2) but only in the absence of canonical G and T. This study indicated that the canonical thymine base is the preferential base partner of methylated purine bases.
- Leonczak, Piotr,Srivastava, Puneet,Bande, Omprakash,Schepers, Guy,Lescrinier, Eveline,Herdewijn, Piet
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p. 13394 - 13409
(2019/11/03)
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- Discovery of 6-phenylpyrimido[4,5- B ][1,4]oxazines as potent and selective Acyl CoA: Diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents
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The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
- Fox, Brian M.,Sugimoto, Kazuyuki,Iio, Kiyosei,Yoshida, Atsuhito,Zhang, Jian,Li, Kexue,Hao, Xiaolin,Labelle, Marc,Smith, Marie-Louise,Rubenstein, Steven M.,Ye, Guosen,McMinn, Dustin,Jackson, Simon,Choi, Rebekah,Shan, Bei,Ma, Ji,Miao, Shichang,Matsui, Takuya,Ogawa, Nobuya,Suzuki, Masahiro,Kobayashi, Akio,Ozeki, Hidekazu,Okuma, Chihiro,Ishii, Yukihito,Tomimoto, Daisuke,Furakawa, Noboru,Tanaka, Masahiro,Matsushita, Mutsuyoshi,Takahashi, Mitsuru,Inaba, Takashi,Sagawa, Shoichi,Kayser, Frank
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supporting information
p. 3464 - 3483
(2014/05/20)
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