Synthesis and Evaluations of “1,4‐Triazolyl Combretacoumarins” and Desmethoxy Analogs

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 O4‐(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 oC, 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 analogs 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 cytotoxicity assays, 1‐phenyl‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐1,2,3‐triazole showed activity in CEM and MDA‐MB‐231 cell lines 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. The antiviral activity of the compounds was unremarkable.

Synthesis and Photophysical Studies on N1‐(Coumarin‐4′′′‐yl)‐C4‐(2′,3′‐dideoxyuridin‐3′‐yl/3′‐deoxythymidin‐3′‐yl)‐oxymethyl‐1,2,3‐triazoles

“…Six 4-azidocoumarin precursors 2 a-f were synthesized from their corresponding 4-hydroxylcoumarins 1 a-f [24,25,26] by following literature procedure. [27] On the other hand, silyl protected O-alkynylated nucleoside precursors 5 a and 5 b were synthesized in two steps starting with the selective protection of C-5'-primary hydroxy group of 2'-deoxyuridine (3 a) and thymidine (3 b) with TBDPSCl in pyridine followed by propargylation of 3'-hydroxyl group of the resulted silylated nucleosides 4 a and 4 b with propargyl bromide and sodium hydride as a base in THF at 0 °C in an overall yields of 85 % and 80 %, respectively. [28] Now, the synthesized azido-and alkynyl-derivatives were used for click chemistry reaction to obtain the coumarin-triazolylmethyl nucleoside conjugates.…”

Base Modifications of Nucleosides via the Use of Peptide‐Coupling Agents, and Beyond

“…As another demonstration of how the results from nucleoside modification chemistry translates to other areas, we developed a novel class of combretacoumarins, for antiproliferation evaluations [88] . The idea was to combine the biologically important A ring of combretastatin A4 with the physiologically important coumarins.…”

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

“…74 µM, MTT assay) showed moderate activity against CEM cells [39,40] ; replacement of coumarin by flavonoid resulted in absence of activity as evidenced by that 1,2,3-triazole-flavonoid hybrids 14…”

“…The antiproliferative SAR of 1,2,3‐triazole‐coumarin hybrids 11 (IC 50 : 7.5–>100 µM, MTT assay) against K562 cells revealed that methoxy group at the para ‐position of coumarin moiety was critical for the activity, and movement of this substituent to meta ‐ or ortho ‐position led to significant loss of activity [ 38 ] ; the carbon spacer between 1,2,3‐triazole and coumarin may have some influence on the activity, and hybrids 12 (IC 50 : 58 µM, MTT assay) and 13 (IC 50 : 74 µM, MTT assay) showed moderate activity against CEM cells [ 39,40 ] ; replacement of coumarin by flavonoid resulted in absence of activity as evidenced by that 1,2,3‐triazole‐flavonoid hybrids 14 (IC 50 : >40 µM, MTT assay) were devoid of activity against HL‐60 cells. [ 41 ] Among them, hybrids 11a–c (IC 50 : 7.5–9.8 µM) were found to be most active against K562 cells and exhibited reactive oxygen species (ROS) production levels similar to that of esculetin.…”