Dissertations and Theses

Date of Award

2018

Document Type

Thesis

Department

Chemistry

First Advisor

Mahesh K. Lakshman

Keywords

ANTICANCER, 1, 4-TRIAZOLYL COMBRETACOUMARINS, COUMARINS

Abstract

Coumarins are natural compounds that have various physiological and therapeutic properties, making them pharmacologically important. Combretastatin A-4 (CA-4) is a microtubule-binding agent that has potent cytotoxic effects against human cell lines. In CA-4 the trimethoxyarene moiety plays a crucial role in its carcinopreventive effect. Thus, we decided to synthesize novel, potential anti-cancer agents called 1,4-triazolyl combretacoumarins, by coupling different coumarins and the functionally relevant group of CA-4 i.e, the trimethoxyarene moiety, via a 1,2,3-triazolyl ring using a copper-catalyzed [3 + 2] azide-alkyne cycloaddition (CuAAC) reaction, which is a very atom-economical reaction. The coupling partners, 4-azidocoumarins, required for making these combretacoumarins were synthesized via a new one-pot approach. In this method, O4-(benzotriazolyl) derivatives of the coumarins are initially prepared in situ by activating the hydroxyl group in 4-hydroxycoumarins using (benzotriazol-1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and DBU, in MeCN. Then, NaN3 is added in order to displace the BtO at the C-4 position, leading to the desired 4-azidocoumarins. The mechanism of the formation of O4-(benzotriazolyl) derivative of 4-hydroxycoumarin has been investigated using 31P NMR, and results indicate that a coumarin-derived phosphonium ion intermediate is formed en route to the O4-(benzotriazolyl)coumarin derivative. The second coupling partner, 5-ethynyl-1,2,3-trimethoxybenzene, was synthesized from 3,4,5-trimethoxybenzaldehyde using the Corey-Fuchs olefination procedure. After various optimizations, it was found that the best conditions for the synthesis of the combretacoumarins is the use of the catalyst [(MeCN)4Cu]PF6, in CH2Cl2/MeOH with 2,6-lutidine as an additive, at 50 oC. Results from a reactivity comparison between PhN3 and 4-azidocoumarin under the aforementioned reaction conditions showed that PhN3 is more reactive. In order to investigate the difference in reactivities of PhN3 and the 4-azidocoumarins, NBO coefficients of azido groups were analyzed using DFT calculations. This revealed that the coefficients of the N1 (the internal nitrogen atom directly connected to the coumarin ring) and N2 did not vary that much from PhN3. Analysis also revealed that the coefficients of the N3 (the terminal nitrogen atom) of one of the coumarin derivatives, 4-azido-7-methoxy-2H-chromen-2-one, and PhN3, were negative with the latter having a more negative charge. In contrast to this, the remaining coumarins all had positive coefficients for the N3. Additionally, the combretacoumarins were evaluated for their antiproliferative and antiviral activities. However, combretacoumarins had solubility limitations, which hindered assessment of biological activity. None of the compounds showed any antiviral activity, and a simple 1-phenyl derivative, obtained from PhN3, was active in CEM and MB-231 cell lines via an apoptotic pathway.

Available for download on Friday, August 28, 2020

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