Metal-free annulation/aerobic oxidative dehydrogenation of cyclohexanones with o-acylanilines: efficient syntheses of acridines

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC02396G, Communication

Gopal Chandru Senadi, Ganesh Kumar Dhandabani, Wan-Ping Hu, Jeh-Jeng Wang
We have identified metal-free reaction conditions for the annulation/aerobic oxidative dehydrogenation of cyclohexanones with o-acylanilines to the corresponding acridine derivatives.

Metal-free annulation/aerobic oxidative dehydrogenation of cyclohexanones with o-acylanilines: efficient syntheses of acridines

Metal-free annulation/aerobic oxidative dehydrogenation of cyclohexanones with o-acylanilines: efficient syntheses of acridines

Gopal Chandru Senadi,^a   Ganesh Kumar Dhandabani,^a  Wan-Ping Hu^b and   Jeh-Jeng Wang*^a  

*Corresponding authors

^aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, Taiwan
E-mail: jjwang@kmu.edu.tw

^bDepartment of Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, Taiwan

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC02396G, 

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02396G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Gopal Chandru Senadi

Kaohsiung Medical University

Department of Medicinal and Applied Chemistry

Kaohsiung, Taiwan

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We have identified metal-free reaction conditions for the annulation/aerobic oxidative dehydrogenation of cyclohexanones with o-acylanilines to the corresponding acridine derivatives. The combination of trifluoroacetic acid (TFA), tert-butyl hydroperoxide (TBHP), dimethylsulfoxide (DMSO) and oxygen (O₂) converted the cyclohexanone derivatives to an aromatic aryl product in moderate to good yields. The experimental results suggest that this process involves an aza-allyl oxidation intermediate.

Prof. Jeh-Jeng Wang

Professor
Department of Medicinal and Applied Chemistry
Kaohsiung Medical University
Kaohsiung, Taiwan

Lab: N842, Bioorganic chemistry Laboratory
Email: jjwang@kmu.edu.tw
Tel: +886-7-3121101
Fax: 886-7-3125339

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Prof. Jeh-Jeng Wang

Education: B.S., Chemistry, National Chung-Hsing University, Taiwan (1975-1979) Ph.D., Chemistry, The Ohio State University, USA (1983-1989) Career: Teaching Assistant, National Chung-Hsing University, Taiwan (1981-1983) Postdoctoral fellow, College of Pharmacy, University of Texas, Austin, USA (1989-1991) Associate Professor, Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Taiwan (1991-2001) Professor, Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Taiwan (since 2001)

 click on imageclick on image

3aa as a pale yellow solid (234 mg, 92%); m.p. 181-182 ° C; IR (neat)max: 1362 cm -1; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.76 (ddd, J = 8.0, 6.8, 1.6 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.66 – 7.56 (m, 3H), 7.49 – 7.41 (m, 4H);

13C NMR (101 MHz, CDCl3) δ 148.66, 147.24, 135.85, 130.37, 129.96, 129.45, 128.40, 128.31, 12

1H NMR

 

13 c nmr

 

//////////Metal-free annulatio, erobic oxidative dehydrogenation, cyclohexanones, o-acylanilines, acridines

Prof. J.J. Wang birthday party - October 21, 2016


Department of Medicinal and Applied Chemistry
Kaohsiung Medical University





Kaohsiung, TAIWAN

Kaohsiung

Municipality in Taiwan

Kaohsiung is a massive port city in southern Taiwan. It's home to many skyscrapers, such as the 248m-tall Tuntex Sky Tower, and is known for its diversity of parks. Its focal point is the Love River, with walking paths and cafes along its banks, and cruise boats navigating its waters. Shopping options range from high-end malls to the Liuhe and Ruifeng night markets

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BRD 2879

BRD2879

BRD-K56962879-001-01-5
CAS 1304750-47-7
Chemical Formula: C30H38FN3O5S
Molecular Weight: 571.7084

3-cyclohexyl-1-(((4R,5R)-8-((3-fluorophenyl)ethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-1-methylurea

3-cyclohexyl-1-[[(4R,5R)-8-[2-(3-fluorophenyl)ethynyl]-2-[(2S)-1-hydroxypropan-2-yl]-4-methyl-1,1-dioxo-4,5-dihydro-3H-6,1$l^{6},2-benzoxathiazocin-5-yl]methyl]-1-methylurea

BRD2879 is a potent and cell-active inhibitor of IDH1-R132H with a markedly different structure from previously reported probes with (IC50 = 50 nM for inhibiting IDH1-R132H enzyme). BRD2879 represents a new structural class of mutant IDH1 inhibitors that, with optimization, may prove useful in the study of this enzyme and its role in cancer

The Eli and Edythe L. Broad Institute of MIT and Harvard (/ˈbroʊd/), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The institute is independently governed and supported as a 501(c)(3) nonprofit research organization under the name Broad Institute Inc.,[1][2] and is partners with Massachusetts Institute of Technology, Harvard University, and the five Harvard teaching hospitals.

Mahmud M. Hussain

Harvard University

Faculty of Arts and Sciences

Cambridge, MA, United States

Mahmud M. Hussain

PAPER

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC₅₀ = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Jason M. Law^†‡, Sebastian C. Stark^†, Ke Liu^†, Norah E. Liang^†‡, Mahmud M. Hussain^†‡§, Matthias Leiendecker^†‡,Daisuke Ito^†, Oscar Verho^†‡, Andrew M. Stern^†, Stephen E. Johnston^†, Yan-Ling Zhang^†, Gavin P. Dunn^∥, Alykhan F. Shamji^*†, and Stuart L. Schreiber^*†‡§

^† Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States

^‡ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States

^§ Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States

^∥ Department of Neurological Surgery, Washington Univeristy School of Medicine, St. Louis, Missouri 63110, United States

ACS Med. Chem. Lett., 2016, 7 (10), pp 944–949

DOI: 10.1021/acsmedchemlett.6b00264

Publication Date (Web): August 18, 2016

Copyright © 2016 American Chemical Society

*E-mail: ashamji@broadinstitute.org., *E-mail: stuart_schreiber@harvard.edu.

People

Stuart L. Schreiber

David Liu

 

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1H NMR (300 MHz, CDCl3, 27 °C) δ 7.88 (d, J = 8.3 Hz, 1H), 7.39-7.27 (m, 3H), 7.22-7.14 (m, 2H), 7.12-7.03 (m, 1H), 4.57 (td, J = 9.5, 2.5 Hz, 1H), 4.35-4.23 (m, 2H), 3.97-3.78 (m, 2H), 3.74-3.60 (m, 2H), 3.51 (ddd, J = 12.3, 9.9, 4.0 Hz, 1H), 3.40 (dd, J = 15.8, 5.1 Hz, 1H), 3.18 (dd, J = 9.9, 2.9 Hz, 1H), 3.12 (dd, J = 14.4, 2.6 Hz, 1H), 2.66 (s, 3H), 2.30-2.16 (m, 1H), 2.06 (d, J = 12.2 Hz, 1H), 1.96 (d, J = 12.1 Hz, 1H), 1.69-1.58 (m,1H), 1.58-1.45 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.40-0.97 (m, 5H), 0.94 (d, J = 7.0 Hz, 3H).

13C NMR (75 MHz, CDCl3, 27 °C) δ 164.20, 160.92, 157.74, 154.80, 134.60, 130.26, 130.15, 129.56, 128.62, 127.82, 127.77, 127.68, 126.90, 124.27, 118.81, 118.50, 116.63, 116.35, 91.32, 88.40, 85.60, 64.86, 58.03, 51.64, 49.88, 48.51, 36.73, 34.51, 34.35, 34.31, 25.72, 25.28, 25.23, 15.76, 15.05.

HRMS (ESI) calc’d for C30H38FN3O5S [M+H]+ : 572.2589. Found: 572.2588.

1H NMR PREDICT

13C NMR PREDICT

REFERENCES

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1
Jason M. Law, Sebastian C. Stark, Ke Liu, Norah E. Liang, Mahmud M. Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M. Stern, Stephen E. Johnston, Yan-Ling Zhang, Gavin P. Dunn, Alykhan F. Shamji, and Stuart L. Schreiber
Publication Date (Web): August 18, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00264

/////////////2-hydroxyglutarate,  allele-selective probe,  AML,  BRD 2879,  cancer,  diversity-oriented synthesis,  glioma,  high-throughput screening,  isocitrate dehydrogenase,  small-molecule probe, BRD2879; BRD-2879; BRD 2879

FC1=CC(C#CC2=CC(O[C@@H](CN(C(NC3CCCCC3)=O)C)[C@H](C)CN([C@@H](C)CO)S4(=O)=O)=C4C=C2)=CC=C1

Rush , few seats, ACS INDUSTRY SYMPOSIUM RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA 11-12 NOVEMBER 2016

ACS INDUSTRY SYMPOSIUM

RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA

11-12 NOVEMBER 2016

click        http://acssymposium.org.in/

For registrations click above link

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