The development of N-functionalized 4-azapodophyllotoxins as novel anticancer agents

Simple item page
dc.contributor.advisorVan Otterlo, Willem Arjen Lodewyken_ZA
dc.contributor.advisorBlackie, Margaret A. L.en_ZA
dc.contributor.authorBotes, Marthinus Gerhardusen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.en_ZA
dc.date.accessioned2020-11-28T17:47:01Zen_ZA
dc.date.accessioned2021-02-01T07:56:27Zen_ZA
dc.date.available2020-11-28T17:47:01Zen_ZA
dc.date.available2021-02-01T07:56:27Zen_ZA
dc.date.issued2020-12en_ZA
dc.descriptionThesis (PhD)--Stellenbosch University, 2020.en_ZA
dc.description.abstractENGLISH ABSTRACT: As malignant carcinomas are one of the world’s leading causes of death in terms of non- communicable diseases, there is a strong need for the development of highly specific antiproliferative agents. Cancer is also an ever-increasing concern in Africa, so the there is also a need to develop anticancer agents that are easily accessible through short synthetic strategies. To this end, we have synthesized a small library of more than 30 novel N-functionalized 4- azapodophyllotoxin analogues and analysed these compounds for their antiproliferative activity. The compounds were synthesized in overall yields of 35-57% for the 4N-aryl derivatives and 18-35% for the 4N-triazolo derivatives. Multicomponent reactions (MCRs) were employed as the main method for the synthesis of the desired scaffolds, after optimizing the procedure to afford the desired compounds from N-functionalized naphthylamines. The N- propargyl analogues were further derivatised through “click” chemistry with a range of different azides. The antiproliferative activity of these compounds were determined against an oesophageal cancer cell line, WHCO1. Two of the 4N-triazolo analogues exhibited inhibitory activities comparable to the known anticancer agent cisplatin (IC50 = 9.2 μM). These were 11-(4-hydroxy-3,5-dimethoxyphenyl)-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,11- dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (231, IC50 = 8.8 μM) and 4-((1- ((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3- triazol-4-yl)methyl)-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin- 1(3H)-one (232, IC50 = 8.3 μM). The 4N-aryl analogues also showed good inhibitory activity, with IC50 values ranging between 11-35 μM, with 4-(4-fluorobenzyl)-11-(4-hydroxy-3,5- dimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (181, IC50 = 11.7 μM) and 4-benzyl-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (185, IC50 = 12.9 μM) the most potent of these compounds. The 4N-propargyl 4- azapodophyllotoxin analogues were also evaluated for their antiproliferative activity, however, the analogues containing the podophyllotoxin and etoposide-derived pendent rings, 174 and 176, respectively) were found to be inactive. The analogues with the modified E-rings were, interestingly, fairly potent inhibitors, as 11-(3,5-dibromo-4-hydroxyphenyl)-4-(prop-2-yn-1-yl)- 4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (177, IC50 = 2.7 μM) and 11-(5-bromo-2- hydroxyphenyl)-4-(prop-2-yn-1-yl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (178, IC50 = 23.3 μM) were active against the WHCO1 cell line. We have also undertaken in silico molecular modelling studies through the use of the Schrödinger Maestro suite, so as to supplement our biological evaluation data and in so doing gain more understanding into the potential active sites that these molecules target. These molecular modelling studies did confirm literature observations that noted the importance of the 4′-hydroxyl group on the pendent E-ring of this class of compounds. This was observed in the favourable docking scores of active compounds such as 177, 181 and 231 against the active site of topoisomerase II. As these compounds strongly mimic etoposide, the molecular modelling studies on the topoisomerase II crystal structure (PDB ID: 3QX3) also gave insight as to why the 4N-triazolo- glycoside 4-azapodophyllotoxins fared better in the antiproliferative studies than the 4N-aryl analogues, as π-π interactions between the triazole ring and the adenosine group on the DNA fragment could be observed. The glycoside groups were stabilized in the solvent exposed region of the active pocket. New insights have thus been gained into the structure-activity relationships of these compounds through the combination of biological evaluation and in silico molecular modelling.en_ZA
dc.description.abstractAFRIKAANS OPSOMMING: Geen Afrikaans opsomming.af_ZA
dc.description.versionDoctorateen_ZA
dc.embargo.terms2021-12-31en_ZA
dc.format.extentxvi, 202 pages : illustrationsen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/109468en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch University, 2020en_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectAntineoplastic agentsen_ZA
dc.subjectCanceren_ZA
dc.subjectChronic diseasesen_ZA
dc.subjectUCTDen_ZA
dc.titleThe development of N-functionalized 4-azapodophyllotoxins as novel anticancer agentsen_ZA
dc.typeThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
botes_development_2020.pdf
Size:
15.9 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
1.71 KB
Format:
Plain Text
Description:
Download
Collections
Doctoral Degrees (Chemistry and Polymer Science)