Browsing by Author "Botes, Marthinus Gerhardus"
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- ItemThe development of N-functionalized 4-azapodophyllotoxins as novel anticancer agents(Stellenbosch : Stellenbosch University, 2020, 2020-12) Botes, Marthinus Gerhardus; Van Otterlo, Willem Arjen Lodewyk; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH 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.
- ItemTowards the synthesis of makaluvamine-analogues(Stellenbosch : Stellenbosch University, 2015-04) Botes, Marthinus Gerhardus; Van Otterlo, Willem A. L.; Pelly, Stephen C.; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Cancer is one of the leading causes of death in developed countries and rising fast as a cause of death in developing countries. The increase of cancer prevalence in developing countries can be attributed to westernisation trends, with lifestyle cancers such as colorectal and lung cancer being amongst the most commonly reported malignant neoplasms. This means that the development of novel methods of treatment is essential in combatting this disease in the developing world. Combinational chemotherapy is one of the best candidates for treatment, but it is reliant on effective compounds targeting different modes of action. It also means that these compounds should be easily and cheaply available. Makaluvamines have been identified as a class of compounds that may have a novel mode of action on top of being known as topoisomerase II inhibitors. This study attempted to devise a short and concise synthetic strategy, based on reported procedures, to construct makaluvamine C analogues. This involved the introduction of a methyl group to an indole intermediate (7,8-dimethoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline), before oxidation to a quarternized pyrroloiminoquinone (7-methoxy-5-methyl-8-oxo-1,3,4,8- tetrahydropyrrolo[4,3,2-de]quinolin-5-ium chloride). The introduction of this methyl group proved problematic, as the indole substrate proved to be difficult to handle and tended to degrade under reaction conditions. The lack of initial success prompted the deviation from the initial route by quarternizing a quinoline intermediate to form a quinolinium iodide salt (4- (dimethoxymethyl)-6,7-dimethoxy-1-methyl-5-nitroquinolin-1-ium iodide). Upon reduction to give 4-(dimethoxymethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-amine, it was discovered that the subsequent ring-closing reaction to produce 7,8-dimethoxy-5-methyl- 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline was still problematic. The synthesis of the target compounds has not yet been successfully completed, but will still be pursued so these compounds can be evaluated for their anticancer activity and have their mode of action tested.