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Synthesis of the first dibenzo-4,12-dithio-8-azacrownophanes containing γ-arylpyridine subunit
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Synthesis of the first dibenzo-4,12-dithio-8-azacrownophanes containing γ-arylpyridine subunit

Tam Pham Thi Thanh, Thao Thuyen Do, Tien Dat Nguyen, Van Boi Luu, Elena I. Polyakova, Thanh Van Tran Thi, Tuan Anh Le, Oct-2020, In: Chemistry of Heterocyclic Compounds, 56, 9, p. 1234–1236

Overview

  • Tam Pham Thi Thanh
  • Thao Thuyen Do
  • Tien Dat Nguyen
  • Van Boi Luu
  • Elena I. Polyakova
  • Thanh Van Tran Thi
  • Tuan Anh Le

Abstract:

We have recently reported the synthesis of new azacrown ethers containing pyridine subunit from 1,5-bis-(2-acetylphenoxy)-3-oxapentane, 1-4 or 1,8-bis(2-acetyl-phenoxy)-3,5-dioxapentane, 5,6 or 2,6-bis[(2-acetylphenyl)-oxymethyl]pyridine using Hantzsch reaction. 7 Among them, several prepared (γ-arylpyridino)azacrown-4 ethers have shown high cytotoxicity toward human cancer cell lines: hepatocellular carcinoma (HepG2), human lung cancer (Lu-1), Rhabdosarcoma (RD), human breast adenocarcinoma (MCF7), human prostate cancer (PC3). 1-7 Based on these results, we have designed and synthesized the first dibenzo-4,12-dithio-8-azacrownophanes 3 containing γ-arylpyridine and dithiocrown ether fragment. In this work, 1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane (1) was effectively prepared from bis(2-mercaptoethyl) ether and 2'-chloroacetophenone by heating in DMSO at 120°C for 17 h with anhydrous K 2 CO 3. 8,9 As shown in Scheme 1, the three reaction components-1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane (1), benzaldehydes 2a,b, and NH 4 OAc-were allowed to react in one step by heating at 120°C in the presence of AcOH as solvent for 15 h. Compounds 3a,b containing a γ-arylpyridine and azadithiocrown moieties were successfully synthesized in about 30-43% yield, depending on the starting benzaldehyde. The structures of dithioazacrown ethers 3a,b were confirmed by 1 H, 13 C NMR, IR, and high-resolution mass spectra. The PASS program 10 predicted neurotransmitter uptake inhibitory activity (79 and 75% probability) and cyclo-hexanone monooxygenase inhibitory activity (64 and 73% probability) for compounds 3a and 3b, respectively. Besides, compound 3a may act as aspulvinone dimethyl-allyltransferase inhibitor (79.1% probability) and gluconate 2-dehydrogenase (acceptor) inhibitor (68.7% probability). Its analog 3b may act as saccharopepsin inhibitor and chymosin inhibitor (62.7% probabilty for both enzymes). In summary, new method for the synthesis of dibenzo-4,12-dithio-8-azacrownophanes from 1,5-bis(2-acetyl-phenylsulfanyl)-3-oxapentane by multicomponent conden-Dibenzo-4,12-dithio-8-azacrownophanes containing γ-arylpyridine subunit and thiocrown fragment were synthesized in one step from 1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane, aryl aldehydes, and ammonium acetate.
1234 We   have   recently   reported   the   synthesis   of   new   azacrown  ethers  containing  pyridine  subunit  from  1,5-bis-(2-acetylphenoxy)-3-oxapentane,1–4    or    1,8-bis(2-acetyl-phenoxy)-3,5-dioxapentane,5,6  or  2,6-bis[(2-acetylphenyl)-oxymethyl]pyridine   using   Hantzsch   reaction.7   Among   them,  several  prepared  (γ-arylpyridino)azacrown-4  ethers  have  shown  high  cytotoxicity  toward  human  cancer  cell  lines:   hepatocellular   carcinoma   (HepG2),   human   lung   cancer    (Lu-1),    Rhabdosarcoma    (RD),    human    breast    adenocarcinoma  (MCF7),  human  prostate  cancer  (PC3).1–7 Based  on  these  results,  we  have  designed  and  synthesized  the first dibenzo-4,12-dithio-8-azacrownophanes 3 containing γ-arylpyridine   and   dithiocrown   ether   fragment.   In   this   work,    1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane    (1) was  effectively  prepared  from  bis(2-mercaptoethyl)  ether  and  2'-chloroacetophenone  by  heating  in  DMSO  at  120°C  for 17 h with anhydrous K2CO3.8,9 As shown in Scheme 1, the three  reaction  components  –  1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane  (1),  benzaldehydes  2a,b,  and  NH4OAc  –  were allowed to react in one step by heating at 120°C in the presence  of  AcOH  as  solvent  for  15  h.  Compounds  3a,b containing  a  γ-arylpyridine  and  azadithiocrown  moieties  were   successfully   synthesized   in   about   30–43%   yield,   depending  on  the  starting  benzaldehyde.  The  structures  of  dithioazacrown  ethers  3a,b  were  confirmed  by  1H, 13C NMR, IR, and high-resolution mass spectra.  The  PASS  program10  predicted  neurotransmitter  uptake  inhibitory  activity  (79  and  75%  probability)  and  cyclo-hexanone  monooxygenase  inhibitory  activity  (64  and  73%  probability)   for   compounds   3a   and   3b,   respectively.   Besides,  compound  3a  may  act  as  aspulvinone  dimethyl-allyltransferase inhibitor (79.1% probability) and gluconate 2-dehydrogenase  (acceptor)  inhibitor  (68.7%  probability).  Its  analog  3b  may  act  as  saccharopepsin  inhibitor  and  chymosin inhibitor (62.7% probabilty for both enzymes).  In  summary,  new  method  for  the  synthesis  of  dibenzo-4,12-dithio-8-azacrownophanes     from     1,5-bis(2-acetyl-phenylsulfanyl)-3-oxapentane  by  multicomponent  conden-Chemistry of Heterocyclic Compounds 2020, 56(9), 1234–1236 Synthesis of the first dibenzo-4,12-dithio-8-azacrownophanes containing γ-arylpyridine subunit Thanh Tam Pham Thi1,2, Thao Thuyen Do1, Tien Dat Nguyen1, Van Boi Luu1, Elena I. Polyakova3, Thanh Van Tran Thi1, Tuan Anh Le1,4* 1 Faculty of Chemistry, VNU University of Science, 19 Le Thanh Tong, Hoan Kiem, Hanoi 100000, Vietnam; e-mail: huschemical.lab@gmail.com 2 Faculty of Pharmacy, Thai Nguyen University of Medicine and Pharmacy,  284 Luong Ngoc Quyen St., Thai Nguyen City, Vietnam; e-mail: phamthithanhtam@tump.edu.vn 3 RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russia; e-mail: alania1980@mail.ru 4 Faculty of Agricultural Technology, VNU University of Engineering and Technology, 144 Xuan Thuy, Cau Giay, Hanoi 100000, Vietnam Submitted July 13, 2020 Accepted July 31, 2020 Dibenzo-4,12-dithio-8-azacrownophanes  containing  γ-arylpyridine  subunit  and  thiocrown  fragment  were  synthesized  in  one  step  from  1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane, aryl aldehydes, and ammonium acetate. Keywords: 1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane,  dibenzo-4,12-dithio-8-azacrownophanes,  thiocrown  ether,  domino  reaction,  Hantzsch reaction.  Published in Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(9), 1234–1236 0009-3122/20/56(9)-1234©2020 Springer Scien

Keyword(s): 1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane, dibenzo-4,12-dithio-8-azacrownophanes, thiocrown ether, domino reaction, Hantzsch reaction.

Article number 1234–1236
Journal Chemistry of Heterocyclic Compounds
Volume 56
Issue number 9
Publication status Published - Oct-2020
ISBN 1573-8353