Department of Chemistry and Polymer Science

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Design and development of novel irreversible GSK-3β inhibitors to address Alzheimer's disease
(Stellenbosch : Stellenbosch University, 2018-03) Hamann, Anton Ruben; Blackie, Margaret A. L.; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Molecular modelling on the GSK-3β protein was carried out to identify a library of suitable electrophilic warhead containing ligands that have the necessary interactions with the binding site. Several series of novel irreversible inhibitors for GSK-3β with potential anti-Alzheimer‟s disease activities were then synthesised. In total, eleven compounds were successfully synthesised. The compounds have been fully characterised using standard spectroscopic and analytical techniques. The scaffold, 5-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}pyrazin-2-amine, was equipped with an α,β-enone Michael acceptor, that allowed for the coupling of various side chains using substitution chemistry. A library of two different series with an internal Michael acceptor was synthesised. The synthesis of the third series that consisted of a terminal Michael acceptor or a halomethylketone was attempted but proved futile. Suzuki-Miyaura chemistry has been thoroughly explored to find the best conditions to offer the products in acceptable yields. Pd(dppf)Cl2 as a catalyst, in a solvent system of toluene:ethanol:water, was found to be the best candidate for the Suzuki-Miyaura reactions to synthesise the aforementioned scaffold. The compounds were tested against the human recombinant GSK-3β and were found to have weak to good activity (GSK-3β IC50 range: 0.12 - >10 μM). The most active compound (GSK-3β IC50: 0.12 μM) consisted of a pyridine ring and the carbonyl of the Michael acceptor is situated directly next to the aminopyrazine core. The results showed that the libraries have the potential to be expanded into a second generation of new compounds.
Design and synthesis of dual-active heterocyclic yybrid inhibitors for β-Hematin and plasmodium falciparum N-Myristoyltransferase
(Stellenbosch : Stellenbosch University, 2016-03) Hay, Jonathan Bruce; Blackie, Margaret A. L.; De Villiers, Katherine A.; Stellenbosch University. Faculty of Engineering. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The current project focused on the design and synthesis of a novel antiplasmodial dual-active conjugate hybrid compound based on an indole scaffold and known antiplasmodial quinolines. The two scaffolds were chosen to target independent pathways in the malaria parasite, namely N-myristoylation and hemozoin formation. Initially, a novel indole compound, ethyl 4-(piperidin-4-yloxy)-1H-indole-2-carboxylate, which would possibly function as a Plasmodium N-myristoylation inhibitor, was synthesised. This would also function as the precursor to the proposed hybrid compound. The synthetic methodology that was employed included the synthesis of starting materials, 2-(benzyloxy)benzaldehyde and ethyl 2-azidoacetate, utilizing well-known benzyl protection and substitution reactions. These compounds were condensed into an azide cinnamate, (Z)-ethyl 2-azido-3-[2-(benzyloxy)phenyl]acrylate, via the Knoevenagel condensation reaction. An alternative method was investigated to obtain the same azide compound via an Arbuzov ylide formation and Horner-Wadsworth-Emmons Wittig-type reaction to obtain an E-stereospecific cinnamate, (E)-ethyl 3-[2-(benzyloxy)phenyl]acrylate, followed by a cerium ammonium nitrate mediated azide addition to afford the azide cinnamate. The azide cinnamate was later subjected to a Hemmetsberger thermal cyclization to form the indole scaffold, ethyl 4-(benzyloxy)-1H-indole-2-carboxylate, followed by a Mitsunobu reaction to afford the novel indole compound. Saponification yielded the carboxylic acid indole derivative, 4-(benzyloxy)-1H-indole-2-carboxylic acid, which was to function as a precursor to the hybrid compound, since an amidation reaction was considered as a possible method for coupling the indole and quinoline scaffolds. Later, 4,7-disubstituted quinoline derivatives were targeted as these would function as the second heterocyclic scaffold for the intended hybrid compound. These were synthesized according to the Gould-Jacobs, Skraup and Doebner-Miller methods, using simple m-substituted anilines as starting materials. The Gould-Jacobs reaction provided the desired 4-chloro-7-substituted quinolines (7-Br, -F, -NO2, -CH3and -OCH3), however, the Skraup and Doebner-Miller reactions only provided the 7-substituted quinolines (7-Br, -CH3 and -OCH3) and required the use of a subsequent oxidation reaction to yield quinoline N-oxides that were later chlorinated to give the desired 4-chloro-7-substituted quinolines. Following the synthesis of the desired quinoline substructures, the 4-chloro-7-substituted quinolines were converted to the desired quinoline pendant groups, N1-7-X-quinolin-4-yl)ethane-1,2-diamine (X = CF3 and Cl), via a chloride substitution reaction using diamino ethane. Preliminary investigations were carried out to obtain the proposed hybrid compound and to ascertain whether an amidation reaction was suitable for the coupling of the two heterocyclic scaffolds. Given time constraints towards the end of the project, only an N, N′-carbonyldiimidazole (CDI) facilitated amidation was investigated. Unfortunately, the approach was not successful. The challenge remains therefore, to utilize the methodologies optimized in this project to investigate heterocyclic hybrid compounds as novel resistance reversers in the treatment of malaria.
Design, synthesis and biological activity studies of 1-aryl-3-(4-methoxybenzyl)ureas as proposed irreversible GSK-3 inhibitors in Alzheimer’s disease therapeutic development
(Stellenbosch : Stellenbosch University, 2019-03) Venter, Jana; Blackie, Margaret A. L.; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterised by memory loss and cognitive decline. No cure has been found for the disease yet, therefore the development of disease-modifying therapeutics (DMTs), which can target the underlying mechanisms of AD, is necessary. Glycogen synthase kinase 3 (GSK-3) has become a promising CNS target, since GSK-3 dysregulation has been shown to play a central role in the multifactorial neuropathogenesis of AD. In this project, a proposed library of structurally-related, irreversible GSK-3β inhibitors was modelled, synthesised, characterised and biologically tested as potential AD drug candidates. The library contained two sets of 1-aryl-3-(4-methoxybenzyl)ureas wherein the incorporated aryl group was a benzothiazole or benzimidazole scaffold, respectively. Different electrophilic warheads were incorporated onto the scaffolds, with the potential to form a covalent, irreversible bond with nucleophilic Cys199 in the GSK-3 ATP pocket. Targeting of Cys199 was suggested to provide increased GSK-3 selectivity, since Cys199 is exchanged with other amino acids in structurally-related enzymes. A library of 10 covalent inhibitors containing the nitrile, halomethylketone (HMK), vinyl ketone, ethynyl ketone and acrylamide electrophilic warheads was successfully synthesised, as well as the reference GSK-3 inhibitor, AR-A014418 (AstraZeneca). The synthetic route commenced with the preparation of the 6-substituted 2-aminobenzothiazoles and 6-substituted 2-aminobenzimidazoles in good yields. Thereafter, the scaffolds were coupled to 4-methoxybenzylamine through carbonyldiimidazole-mediated urea formation, which afforded excellent yields for the benzothiazoles and moderate yields for the benzimidazoles, proposedly due to tautomeric effects in the latter. These ureas were further modified in position 6 of the benzazole scaffolds, to incorporate the respective electrophilic warheads. The GSK-3β inhibitory activity results were promising, with high activities measured for the nitrilesubstituted ureas and the HMK-substituted benzimidazole urea. In comparison to the reference GSK-3 inhibitor, which displayed an IC50 value of 0.072 ± 0.043 μM in the assay, the best IC50 value obtained in the library was 0.086 ± 0.023 μM, observed for 1-(6-cyano-1H-benzo[d]imidazol-2-yl)-3-(4- methoxybenzyl)urea. In general, the benzimidazole series displayed better IC50 values than the equivalent inhibitors in the benzothiazole series. Although an initial assay was carried out to ascertain whether the newly synthesised inhibitors were in fact irreversible inhibitors, the results remain ambiguous and further study is required to confirm this hypothesis. In conclusion, highly active GSK-3β inhibitors were successfully developed and may potentially contribute to future AD drug development.
The 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.
Investigating the formation of multicomponent crystals of antiplasmodial agents
(Stellenbosch : Stellenbosch University, 2019-03) Clements, Monica Jade; Blackie, Margaret A. L.; Le Roex, Tanya; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The aim of this project was to explore the formation of multicomponent crystals of some known, as well as some novel, antiplasmodial agents and investigate and compare structures and properties of the antiplasmodials and the multicomponent crystals that they form. A series of five known 4-aminoquinoline antiplasmodial agents were chosen and the formation of multicomponent crystals with these compounds was investigated. The use of molecular electrostatic potential surfaces (MEPS) to calculate molecular complementarity with a specific coformer allowed us to rank a list of coformers according to the probability of forming multicomponent crystals with each 4- aminoquinoline. A total of nineteen multicomponent forms were obtained by liquid-assisted grinding, and these were characterised by PXRD, IR, TGA and DSC. Possible reasons are given for why two of the five 4-aminoquinolines yielded only amorphous multicomponent products, while three yielded crystalline products. Additionally, a brief discussion is given for the reasonably low success rate (38%) of the MEPS method for coformer selection. Attempts were then made to synthesise a series of novel aminoferrocene-containing lapatinib analogues so that the abovementioned knowledge could be applied to a novel system. While, we successfully achieved the synthesis of the precursor fragments, the key reaction that coupled the aminoferrocene fragment to the lapatinib core – the Suzuki-Miyaura reaction – proved more challenging than expected. After substantial effort, the desired product was obtained (as detected by LC-MS), however it could not be isolated, most likely due to low yields. The use of an amine or amide linker (instead of a direct carbon-carbon bond) was also investigated, however these attempts were also unsuccessful. A series of 6-substituted quinazolin-4(3H)-ones, formed serendipitously during the synthesis of the lapatinib analogues, were also studied for their ability to form multicomponent crystals. The MEPS method to select coformers was applied and liquid-assisted grinding was used to form eight novel multicomponent crystals. Interestingly, only one of the quinazolinone derivatives formed multicomponent crystals with the chosen coformers, while the remaining three yielded only mixtures of starting materials. Possible explanations for this were explored and it is clear that there are additional factors that play a larger role than initially thought. This study shows that quinoline- and quinazolinone-based antiplasmodial agents warrant further attention for the formation of multicomponent crystals. The work described in this thesis provides a greater understanding of the ability of these molecules to form multicomponent crystals. Together with similar studies, this knowledge could be applied to related systems, which would one day allow for accurate predictions and the formation of multicomponent crystals of antiplasmodial agents with tailored properties.
Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor
(Stellenbosch : Stellenbosch University, 2017-12) Brigg, Siobhan Ernan; Pelly, Stephen, C.; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: HIV-1 remains the worst pandemic faced by mankind since its discovery as the causative agent of AIDS in the early 1980s. An enormous amount of research has been done to find a cure, but to date there has been no success and resistance is widespread among the available treatment. This project focused on the development of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a rational design approach. The lead compound, ethyl 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole-2-carboxylate, was shown to have low nano-molar potency against HIV-1 (IC50 = 16 nM), however it had two main shortcomings which needed to be addressed; poor resistance profile and poor acid stability. Previous research had shown the resistance profile could be improved by introducing meta substitution on the phenyl moiety which interacts with Tyr181 of the NNRTI binding pocket (NNIBP). We were successful in synthesising several meta substituted phenyl derivatives of the lead compound and these were shown to be equally as potent as the lead compound. Their activity against resistant strains is yet to be determined as we are awaiting the results from biological testing. The presence of an acid labile methyl ether functionality on the molecule which was susceptible to an acid catalysed indole mediated SN1 substitution in aqueous acidic medium meant that the lead compound could never be considered as a candidate for an orally available drug. The methyl ether moiety was exchanged for a sulfide moiety and several of these derivatives were successfully synthesised. Acid stability tests showed that we were successful in our endeavour to improve the acid stability, offering an advantage over the lead compound despite a slight reduction in potency. However to completely eliminate the possibility of substitution, we replaced the methyl ether moiety for an ethyl group, successfully synthesising ethyl 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxylate and 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxamide and we are currently awaiting the results from biological testing to determine whether this derivative is active against HIV-1. The functionality in the 2-position of the indole was also investigated through the synthesis of 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole and 5-chloro-3-((methylthio)(phenyl)methyl)-1H-indole. These derivatives lacking a group in the 2-position of the indole showed significant reduction in potency. Replacement of the ethyl ester for an isobutyl ester to give isobutyl 5-chloro-3-((3,5-dimethylphenyl)(methylthio)methyl)-1H-indole-2-carboxylate, showed some maintenance of potency, however the larger side chain was not well accommodated in the NNIBP. The presence of a chiral centre on the lead compound, and all derivatives synthesised in the project, resulted in our final aim; we set out to develop a method for resolving these enantiomers. Unfortunately, although we employed a variety of different strategies, including the use of chiral auxiliaries and the classical resolution method of attempting to make diastereomeric salts, we were not successful in achieving this aim.
Synthesis and biological evaluation of novel ferroquine and phenylequine analogues
(Stellenbosch : Stellenbosch University, 2013-03) Jacobs, Leon; Blackie, Margaret A. L.; De Villiers-Chen, Katherine; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
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Synthesis of fused heterocyclic aromatic compounds as potential antiplasmodial agents
(Stellenbosch : Stellenbosch University, 2017-12) Jacobs, Leon; Blackie, Margaret A. L.; Pelly, S. C.
ENGLISH ABSTRACT: 3-Methyl benzofuran antiplasmodial compounds have been described in literature and and synthesis of heterocyclic derivatives forms the basis of this project. These benzofuran compounds were synthesized with the primary role as effective inhibitors of the enzyme Plasmodium falciparum N-Myristoyl transferase (PfNMT). PfNMT plays an important enzymatic function in the majority of all living organisms, facilitating the myristoylation of N-terminal glycine residues of proteins that serve many functions in vivo, and is considered vital to the viability of not only most organisms, but P. falciparum too. The rationale behind the key features of these antiplasmodial compounds include the heterocyclic scaffold that induces π – π stacking with amino acid residues at the active site of PfNMT, aromatic amide and ester groups also necessary for π – π stacking and a piperidinium salt coupled to the heterocycle, providing a salt-bridge interaction with neighboring amino acid residues. Five different heterocycles were synthesized with the primary function of replacing the benzofuran moiety in order to ascertain which heterocyclic system is the most efficacious. We synthesized indole, 3-methyl indole, 1-methyl benzimidazole, benzoxazole and benzothiophene scaffolds, each containing an ester group at the C2-position necessary for transesterification and amidation reactions, as well as a phenolic group at the C4-position (C7-position for the benzimidazole scaffold) required for the introduction of a piperidine group. The Boc-protected piperidine group was introduced first, followed by esterification reactions with 2-phenylethanol, benzyl alcohol and 1-naphthalenemethanol. Amidation reactions were also carried out with 2-phenethylamine, benzylamine, 1-naphthylmethylamine and 4-(aminomethyl)pyridine. The synthesis of each series of heterocyclic antiplasmodials was realized after the final Boc-deprotection step, providing all the compounds in salt form. These compounds were sent for whole-cell testing against a P. falciparum chloroquine sensitive strain (NF54) with the intention to prove which heterocycle and aromatic ester or amide substituent improves the efficacy the most, and validate the importance of a methyl group on the 3-methyl indole and 1-methyl benzimidazole scaffold when comparing the efficacy of analogous esters and amides. The results indicated that the benzoxazole series of compounds were inactive and the 3-methyl indole series are the most active which returned IC50 values of 0.56 – 6.1 μM respectively, but is trailed closely in efficacy by the indole (IC50 values of 0.83 – 6.5 μM) and benzothiophene (IC50 values of 0.71 – 5.9 μM) series of compounds. The 1-methyl benzimidazole series of compounds were the least active with IC50 values between 7.4 – 13.3 μM apart from one compound indicating an IC50 value of 1.1 μM.
Synthesis of triazole-linked chloroquinoline derivatives as novel antimalarial agents
(Stellenbosch : Stellenbosch University, 2013-03) Taleli, Lebusetsa; Van Otterlo, William A. L.; Blackie, Margaret A. L.; Pelly, Stephen; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
Aminoquinolines are important class of drugs that have been used for malaria chemotherapy for centuries. However, long-term exposure to these drugs leads to extensive spread of drug resistance. As such, modified chloroquinoline derivatives are being studied as alternative antimalarial agents with the possibility to overcome drug resistance associated with chloroquine analogues. In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazole ring to an ethyl and propyl carbon spacer with a distal amine motif were designed and synthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. The compounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyne precursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncoupling in the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). These compounds have been characterized by the combination of NMR, ESI+ HRMS and IR spectroscopic methods. The antiplasmodial activity of the compounds was investigated in vitro against P. falciparum strain NF54 using chloroquine as a reference drug together with a standard antimalarial drug artesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possess promising potency by way of the inhibition concentrations less than 250 nM with the lowest being 28 nM. The observed activities have been ascribed to the overall modifications such as the introduction of a triazole linker and changing of carbon chain length as these were the variables. The compounds are accordingly under further biological investigations and only the chloroquine sensitive results are reported in this work.
Towards 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.

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