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Achary, R.,Mathi, G.,Kim, S.,Hwang, J.,Kim, P. Royal Society Chemistry 2018 Organic & Biomolecular Chemistry Vol.16 No.9
<P>Treatment of the trifluoroacetyl enamides of dihydroisoquinolines 2 with diverse Grignard reagents afforded tertiary trifluoromethyl-carbinols 4 by facilitating the addition of tertiary carbinols to the beta-carbon of enamides 2. Based on the confirmed formation of vinylogous amides 3, the transformation likely proceeds via unique acyl group rearrangement to the beta-carbon of the enamide and subsequent nucleophilic addition of the Grignard reagent. Given the synthetic utility and novelty of this reaction, this work may open new avenues for the synthesis of pharmaceutically important tertiary trifluoromethylcarbinols on cyclic enamide systems.</P>
Achary, Raghavendra,Jung, In-A,Lee, Hyeon-Kyu American Chemical Society 2018 Journal of organic chemistry Vol.83 No.7
<P>A tandem process, involving Rh(III)-catalyzed oxidative C-H olefination of enantiomerically enriched 4-aryl-benzo-1,3-sulfamidates and subsequent intramolecular aza-Michael cyclization has been developed. The reaction produces <I>trans</I>-benzosulfamidate-fused-1,3-disubstituted isoindolines as major products, in which the configurational integrity of the stereogenic center in the starting material is preserved. Further transformations of the benzosulfamidate-fused-1,3-disubstituted isoindolines are described.</P> [FIG OMISSION]</BR>
Achary, Raghavendra,Mathi, Gangadhar Rao,Lee, Dong Ho,Yun, Chang Soo,Lee, Chong Ock,Kim, Hyoung Rae,Park, Chi Hoon,Kim, Pilho,Hwang, Jong Yeon Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.10
<P><B>Abstract</B></P> <P>In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, <B>28</B>, <B>29</B>, <B>36</B>, and <B>42</B> showed promising anti-ALK activities in enzymatic- and cell-based assays. <I>In vivo</I> H3122 xenograft model study showed that compound <B>29</B> effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors
Achary, Raghavendra,Yun, Jeong In,Park, Chi Min,Mathi, Gangadhar Rao,Lee, Joo Yun,Ha, Jae Du,Chae, Chong Hak,Ahn, Sunjoo,Park, Chi Hoon,Lee, Chong Ock,Hwang, Jong Yeon,Yun, Chang-Soo,Jung, Hee Jung,Ch Pergamon 2016 Bioorganic & medicinal chemistry Vol.24 No.2
<P>Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378. (C) 2015 Elsevier Ltd. All rights reserved.</P>
Achary, Raghavendra,Jung, In-A,Son, Se-Mi,Lee, Hyeon-Kyu American Chemical Society 2017 Journal of organic chemistry Vol.82 No.14
<P>A new method for the direct, stereoselective synthesis of highly functionalized 1,3-disubstituted isoindolines 6 from enantiomerically enriched cyclic 4-aryl-sulfamidate-5-carboxylates (5) is described. The process involves sulfamidate directed, Rh(III)-catalyzed tandem ortho CH olefination of the 4-aryl-sulfamidate-5-carboxylates and subsequent cyclization by aza-Michael addition. In the reaction, which generates trans-1,3-disubstituted isoindolines exclusively, the configurational integrity of the stereogenic center in the starting cyclic sulfamidate is completely retained in the product. Examples are provided which show that the cyclic sulfamidate moiety not only serves as a chiral directing group but also as a versatile handle for further functionalization of the generated isoindoline ring system.</P>
Raghavendra Achary,김슬기,최유리,Gangadhar Rao Mathi,김현진,황종연,김필호 대한화학회 2019 Bulletin of the Korean Chemical Society Vol.40 No.3
A mild one-pot and metal-free condition was discovered to implement two different alkyl groups chemoselectively on 1-methyl-3,4-dihydroisoquinoline (1-Me-DHIQ), one at the nitrogen another at the C1-methyl group. This chemistry is compatible with various DHIQs as well as alkyl halides. Application of this chemistry facilitated the concise syntheses of methopholine, (±)-homolaudanosine, and (±)-dysoxyline, requiring only two steps from 6,7-dimethoxy-1-Me-DHIQ.
Pyrazolo[3,4‐ d ]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors
Yeom Hyesu,Achary Raghavendra,Choi Yunha,Park Chi Hoon,Lee Joo‐Youn,Lee Heung Kyoung,Kim Pilho,Cho Sung Yun 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.4
4,6-Disubstituted pyrazolo[3,4-d]pyrimidine derivatives were explored as irreversible Bruton’s tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turned out that introducing 1-acrylamido-4-aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3-acrylamido-aniline (1j) as 4-position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell-based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B-cell-mediated hematologic cancers.
Kim, Hyeong Rae,Achary, Raghavendra,Lee, Hyeon-Kyu American Chemical Society 2018 Journal of organic chemistry Vol.83 No.19
<P>Dynamic kinetic resolution (DKR)-driven asymmetric transfer hydrogenation of 5-alkyl cyclic sulfamidate imine produces the corresponding sulfamidate with excellent levels of diastereo- and enantioselectivity by employing a HCO<SUB>2</SUB>H/DBU mixture as the hydrogen source in the presence of the Noyori-type chiral Rh-catalyst at room temperature for 1 h. In this process, DKR was induced by DBU-promoted rapid racemization of the substrate. Stereoselective transformations of the resulting cyclic sulfamidates to functionalized enantiomerically enriched 1,2-amino alcohol and chiral amine substances are also described.</P> [FIG OMISSION]</BR>
Jang, Y.J.,Achary, R.,Lee, H.W.,Lee, H.J.,Lee, C.K.,Han, S.B.,Jung, Y.S.,Kang, N.S.,Kim, P.,Kim, M. Elsevier/North-Holland 2014 ANTIVIRAL RESEARCH Vol.107 No.-
A target-free approach was applied to discover anti-influenza viral compounds, where influenza infected Madin-Darby canine kidney cells were treated 7500 different small organic chemicals individually and reduction of virus-induced cytopathic effect was measured. One of the hit compounds was (Z)-1-((5-fluoro-1H-indol-3-yl)methylene)-6-methyl-4-thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-one (15a) with half-maximal effective concentrations of 17.4-21.1μM against influenza A/H1N1, A/H3N2 and B viruses without any cellular toxicity at 900μM. To investigate the structure-activity relationships, two dozens of the hit analogs were synthesized. Among them, 15g, 15j, 15q, 15s, 15t and 15x had anti-influenza viral activity comparable or superior to that of the initial hit. The anti-influenza viral compounds efficiently suppressed not only viral protein level of the infected cells but also production of viral progeny in the culture supernatants in a dose-dependent manner. Based on a mode-of-action study, they did not affect virus entry or RNA replication. Instead, they suppressed viral neuraminidase activity. This study is the first to demonstrate that dihydrofuropyridinones could serve as lead compounds for the discovery of alternative influenza virus inhibitors.