Synthesis Of 1,4-Triazolyl Combretacoumarins As Potential Anticancer Agents

<p>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 <em>1,4-triazolyl combretacoumarins</em>, by coupling different coumarins and the functionally relevant group of CA-4 i.e, the trimethoxyarene moiety, <em>via</em> 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 <em>via</em> a new one-pot approach. In this method, <em>O</em>⁴-(benzotriazolyl) derivatives of the coumarins are initially prepared <em>in situ</em> 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 <em>O</em>⁴-(benzotriazolyl) derivative of 4-hydroxycoumarin has been investigated using ³¹P NMR, and results indicate that a coumarin-derived phosphonium ion intermediate is formed <em>en route</em> to the <em>O</em>⁴-(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 <em>N</em>1 (the internal nitrogen atom directly connected to the coumarin ring) and <em>N</em>2 did not vary that much from PhN₃. Analysis also revealed that the coefficients of the <em>N</em>3 (the terminal nitrogen atom) of one of the coumarin derivatives, 4-azido-7-methoxy-2<em>H</em>-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 <em>N</em>3. 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 <em>via </em>an apoptotic pathway.</p>

Name thesis:degree_name

Master of Science (M.S.)

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2018

Author dc:creator

• Khandaker, Tashrique A.

Contributors dc:contributor

• Mahesh K. Lakshman

• ANTICANCER
• 1
• 4-TRIAZOLYL COMBRETACOUMARINS
• COUMARINS
• Medicine and Health Sciences
• Physical Sciences and Mathematics

Repository record dc:identifier

https://academicworks.cuny.edu/cc_etds_theses/764

OAI identifier oai:identifier

oai:academicworks.cuny.edu:cc_etds_theses-1778