Organic chemistry in South Africa

CITATION: Van Otterlo, W. A. L. 2020. Organic chemistry in South Africa. Arkivoc, iii:1-3, doi:10.24820/ark.5550190.p001.480.The original publication is available at https://www.arkat-usa.orgENGLISH ABSTRACT: No abstract available.Publisher's versio

Atroposelective NiII‐Catalyzed Cross‐Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher‐Order Zincates

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3]2−Mg(THF)22+. The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions

Cyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions

CITATION: Morgans, G. L. et al. 2020. Cyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions. Arkivoc, iii:4-23, doi:10.24820/ark.5550190.p011.221.The original publication is available at https://www.arkat-usa.orgSeveral N-phenacyl enaminones, prepared by Eschenmoser sulfide contraction between Nphenacylpyrrolidine-2-thiones and a range of substituted phenacyl halides, were transformed into 2,3- dihydro-1H-pyrrolizines when treated with acetic acid or silica gel. Yields of the bicyclic products were in the range 57–100% depending on the route followed. Some further reactions of the newly formed pyrrole rings are also reported.Publisher's versio

In vitro analysis of the combinatory effects of novel aminonaphthoquinone derivatives and curcumin on breast cancer progression

CITATION: Pereira, Melanie C. et al. 2020. In vitro analysis of the combinatory effects of novel aminonaphthoquinone derivatives and curcumin on breast cancer progression. Anticancer Research, 40(1):229-238, doi:10.21873/anticanres.13944.The original publication is available at: https://pubmed.ncbi.nlm.nih.govBackground/aim: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. Materials and methods: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. Results: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. Conclusion: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.Publisher's versio

Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups

CITATION: Van der Westhuyzen, A. E. et al. 2020. Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups. Arkivoc, v:129-147, doi:10.24820/ark.5550190.p011.412.The original publication is available at https://www.arkat-usa.orgDue to their involvement in almost all stages of cellular life, kinase biomolecular catalysts have been linked to cancer development and, thus, remain attractive drug targets for cancer therapeutics. 6-(3ꞌ-Hydroxypropyl)-, 6-(2ꞌ-hydroxyethyl)-, 6-(2ꞌ-propynyl)- and 6-(3ꞌ-propanenitrile)-pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were synthesized as potential small molecule EGFR kinase inhibitors. The pyrrolocarbazole compounds were synthesized by way of a Diels-Alder approach involving N-alkylated 2-vinyl-1H-indole and maleimide as starting materials followed by aromatization with MnO2.Publisher's versio

Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors

Please cite as follows: Chakravorty, S. et al. 2014. Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors. South African Journal of Chemistry, 67:71–79.The original publication is available at http://www.journals.co.za/sajchemSubstituted anthranilic acid and piperazines were used as building blocks to prepare two libraries of compounds, with the aim being that they would exhibit biochemical activity as small molecule kinase inhibitors. The synthesized anthranilamidepiperazine compounds were subsequently tested against a panel of kinases including EGFR, Abl, Akt and Aurora B.http://www.scielo.org.za/scielo.php?script=sci_abstract&pid=S0379-43502014000100012&lng=en&nrm=iso&tlng=enPublisher's versio

Covalent allosteric inhibitors of Akt generated using a click fragment approach

Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties

Fluorophore Labeled Kinase Detects Ligands That Bind within the MAPK Insert of p38α Kinase

The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38α mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38α, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38α signaling pathway

A review on recent syntheses of Amaryllidaceae alkaloids and isocarbostyrils (time period mid-2016 to 2017)

CITATION: Van Otterlo, W. A. L. & Green, I. R. 2018. A review on recent syntheses of Amaryllidaceae alkaloids and isocarbostyrils (time period mid-2016 to 2017). Natural Product Communications, 13(3):255 - 277.The original publication is available at https://us.sagepub.com/en-us/nam/natural-product-communications/journal203650Alkaloids from the Amaryllidaceae have become valuable targets for synthetic organic chemists, mainly due to their wide variety of bioactivities and potential for utilization in medicinal chemistry ventures. In addition, the structural complexity of a number of these alkaloids has also been a reason for the interest in these compounds. In this review, the last 18 months of literature was perused and synthetic highlights have been presented here, with the hope to further focus attention on this interesting class of compounds and to encourage others to synthesize these compounds and their derivatives and/or analogues. The review contains examples of syntheses from most of the important alkaloid scaffold classes previously isolated from the Amaryllidaceae, namely: lycorine, crinine, galanthamine, tazettine, montanine, phenanthridone, phenanthridine, plicamine, mesembrine and some minor scaffolds (like gracilamine).Publisher's versio

1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation

4 p.-4 fig.-1 tab.Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer’s disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 µM) and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 µM) displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ± 0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.This research was financially supported by the National Research Foundation, South Africa (Innovation Master’s Scholarship 2017–2018), Stellenbosch University and MINECO (Grant No. SAF2016-76693-R).N