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. 2019 Sep 8;2019(33):5610-5623.
doi: 10.1002/ejoc.201900569. Epub 2019 Aug 7.

Synthesis and Evaluations of "1,4-Triazolyl Combretacoumarins" and Desmethoxy Analogues

Tashrique A Khandaker  1 , Jessica D Hess  2 , Renato Aguilera  2 , Graciela Andrei  3 , Robert Snoeck  3 , Dominique Schols  3 , Padmanava Pradhan  1 , Mahesh K Lakshman  1   4
Affiliations

Synthesis and Evaluations of "1,4-Triazolyl Combretacoumarins" and Desmethoxy Analogues

VSports在线直播 - Tashrique A Khandaker et al. European J Org Chem. .

Abstract

1,4-Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3-triazole. For this, 4-azidocoumarins were accessed by a sequential two-step, one-pot reaction of 4-hydroxycoumarins with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN3. In the reaction with BOP, a coumarin-derived phosphonium ion intermediate seems to form, leading to an O 4-(benzotriazolyl)coumarin derivative. For the CuAAC reaction of azidocoumarins with 5-ethynyl-1,2,3-trimethoxybenzene, catalytic [(MeCN)4Cu]PF6 in CH2Cl2/MeOH with 2,6-lutidine, at 50 °C, was suitable. The 4-azidocoumarins were less reactive as compared to PhN3 and the NBO coefficients of the azido groups were compared by DFT analysis. Compound solubility was a problem in biological assays. On the basis of the biological and solubility data of one 1,4-triazolyl combretacoumarin, four analogues lacking one or two methoxy groups were synthesized. Reactivity differences among the phenylacetylenes were noted and the NBO coefficients of the alkynes were compared by DFT analysis. In antiproliferative assays, 1-phenyl-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole showed activity in CEM and MDA-MB-231 cell lines, possibly by apoptosis. The desmethoxy 6-bromo-4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one also showed cytotoxicity against the two cell lines, but this did not appear to be consistent with apoptosis VSports手机版. The antiviral activity of the compounds was unremarkable. .

Keywords: Coumarin; CuAAC; alkyne; combretastatin; copper; triazole V体育安卓版. .

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Figures

Figure 1
Figure 1
Structures of coumarin, CA4, and several biologically active coumarin derivatives and CA4 analogs.
Figure 2
Figure 2
Structures of precursors to two isomeric combretacoumarins.
Scheme 1
Scheme 1
A potential one‐pot C4 hydroxyl group activation and replacement with azide.
Figure 3
Figure 3
Structures of seven 4‐azidocoumarins that were synthesized (total reaction times for the two steps are shown).
Scheme 2
Scheme 2
Possible pathways for the formation of intermediate 2.
Figure 4
Figure 4
Monitoring the reaction of 4‐hydroxycoumarin (1) with BOP and DBU in MeCN by 31P{1H} NMR.
Scheme 3
Scheme 3
Synthesis of 5‐ethynyl‐1,2,3‐trimethoxybenzene (12) and the CuAAC reaction.
Figure 5
Figure 5
Products prepared via CuAAC reactions of azidocoumarins and PhN3 with 5‐ethynyl‐1,2,3‐trimethoxybenzene.
Figure 6
Figure 6
Desmethoxy “1,4‐combretacoumarin” analogs prepared from 4‐azido‐6‐bromo‐2H‐chromen‐2‐one (6).
Figure 7
Figure 7
Dose‐response curves for CEM and MB‐231 cells.
Figure 8
Figure 8
Apoptosis assays on compounds 20 and 23‐treated CEM cells (panels A and B, respectively) using annexin V‐FITC and propidium iodide. Orange bars: apoptosis and blue bars: necrosis.
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