Browsing by Author "Van Otterlo, Willem A. L."
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- ItemAlkaloids with activity against the Zika virus vector Aedes aegypti (L.) - crinsarnine and sarniensinol, two new crinine and mesembrine type alkaloids isolated from the South African Plant Nerine sarniensis(MDPI, 2016-10-27) Masi, Marco; Cala, Antonio; Tabanca, Nurhayat; Cimmino, Alessio; Green, Ivan R.; Bloomquist, Jeffrey R.; Van Otterlo, Willem A. L.; Macias, Francisco A.; Evidente, AntonioTwo new Amaryllidaceae alkaloids, belonging to the mesembrine- and crinine-types, named crinsarnine (1) and sarniensinol (2), were isolated from the dried bulbs of Nerine sarniensis together with bowdensine (3), sarniensine (4), hippadine (5) and 1-O-acetyl-lycorine (6). Crinsarnine (1) and sarniensinol (2) were characterized using spectroscopic and chiroptical methods as (1S,2S,4aR,10bS)-2,7-dimethoxy-1,2,3,4,4a,6-hexahydro-5,11b-ethano[1,3]dioxolo-[4,5-j]phenanthridin- 1-yl acetate and (6-(3aR,4Z,6S,7aS)-6-methoxy-1-methyl-2,3,3a,6,7,7a-hexa-hydro-1H-indol-3a-yl)benzo [d][1,3]dioxol-5-yl)methanol, respectively. Furthermore, the complete spectroscopic characterization of bowdensine (3) is reported for the first time. Compounds 1–6 were evaluated against the Orlando reference strain of Aedes aegypti. None of compounds showed mortality against 1st instar Ae. aegypti larvae at the concentrations tested. In adult topical bioassays, only 1 displayed adulticidal activity with an LD50 = 2.29 ± 0.049 µg/mosquito. As regards the structure-activity relationship, the pretazettine and crinine scaffold in 2 and 4 and in 1 and 3 respectively, proved to be important for their activity, while the pyrrole[de]phenanthridine scaffold present in 5 and 6 was important for their reactivity. Among the pretazettine group compounds, opening of the B ring or the presence of a B ring lactone as well as the trans-stereochemistry of the A/B ring junction, appears to be important for activity, while in crinine-type alkaloids, the substituent at C-2 seems to play a role in their activity
- ItemCyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions(ARKAT USA, 2020) Morgans, Garreth L.; Fernandes, Manuel A.; Van Otterlo, Willem A. L.; Michael, Joseph P.ENGLISH ABSTRACT: Several 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.
- ItemFluorophore labeled kinase detects ligands that bind within the MAPK insert of p38α kinase(Public Library of Science, 2012-07-02) Getlik, Matthaus; Simard, Jeffrey R.; Termathe, Martin; Grutter, Christian; Rabiller, Matthias; Van Otterlo, Willem A. L.; Rauh, DanielENGLISH ABSTRACT: 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. © 2012 Getlik et al.
- ItemIn vitro analysis of the combinatory effects of novel aminonaphthoquinone derivatives and curcumin on breast cancer progression(International Institute of Anticancer Research, 2020-01) Pereira, Melanie C.; Mohammed, Raushaan; Van Otterlo, Willem A. L.; De Koning, Charles B.; Davids, HajierahBackground/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.
- ItemOrganic chemistry in South Africa(ARKAT USA, 2020) Van Otterlo, Willem A. L.ENGLISH ABSTRACT: No abstract available.
- ItemA review on recent syntheses of Amaryllidaceae alkaloids and isocarbostyrils (time period mid-2016 to 2017)(Sage Publishing, 2018) Van Otterlo, Willem A. L.; Green, Ivan R.Alkaloids 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).
- ItemSynthesis and antimicrobial activity of the essential oil compounds (E)- and (Z)-3-hexenyl nonanoate and two analogues(University of KwaZulu-Natal, 2012) Chakravorty, Santanu; Rayner, Matthew K.; De Koning, Charles B.; Van Vuuren, Sandy F.; Van Otterlo, Willem A. L.The synthesis of (E)- and (Z)-3-hexenyl nonanoate, known constituents of essential oil containing plants, and two related compounds is reported. These compounds were assembled from nonanoyl chloride or nonanoic acid and the respective alcohols. In particular, it was found that the use of triethylamine as a co-solvent was necessary to avoid acid-mediated isomerization of the alkenes, which resulted in an inseparable mixture of products. The antimicrobial activity of the four hexenyl and hexyl nonanoate compounds was undertaken using microdilution minimum inhibitory concentration (MIC) analysis against eight test microorganisms. All four compounds demonstrated activity, with (E)-3-hexenyl nonanoate 1B: having the highest inhibition (MIC value of 0.45 mg mL-1) against Pseudomonas aeruginosa ATCC 27858. Furthermore, this compound demonstrated the highest broad-spectrum activity (mean MIC value of 1.24 ± 0.50 mg mL-1) with noteworthy activity against all pathogens tested.
- ItemSynthesis of 2-substituted tetrahydroisoquinolin-6-ols: potential scaffolds for estrogen receptor modulation and / or microtubule degradation(ARKAT USA, 2019) Mabank, Tanya; Alexandre, Kabamba B.; Pelly, Stephen C.; Green, Ivan R.; Van Otterlo, Willem A. L.ENGLISH ABSTRACT: 6-Methoxytetrahydroisoquinoline hydrochloride was converted into four small libraries of substituted ureas, thioureas, sulfonamides and N-aryls, using the tetrahydroisoquinoline nitrogen as the scaffold-linking atom. Some of the compounds were evaluated for their ability to inhibit cell proliferation using the MCF7 (invasive ductal carcinoma) cell line.
- ItemSynthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors(South African Chemical Institute, 2014-03) Chakravorty, Santanu; Klein, Hanna F.; Hodson, Luke E.; Rabillier, Matthias; Fang, Zhizhou; Richters, Andre; Pelly, Stephen C.; Rauh, Daniel; Van Otterlo, Willem A. L.Substituted 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.
- ItemSynthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups(ARKAT USA, 2020) Van der Westhuyzen, Alet E.; Hadjegeorgiou, Kathy; Green, Ivan R.; Pelly, Stephen C.; Van Otterlo, Willem A. L.ENGLISH ABSTRACT: Due 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.
- ItemSynthesis of triazole-linked 2-trichloromethylquinazolines and exploration of their efficacy against P. falciparum(University of KwaZulu-Natal, 2013) Hamann, Anton R.; De, Kock Carmen; Smith, Peter J.; Van Otterlo, Willem A. L.; Blackie, Margaret A. L.Using 2-trichloromethylquinazoline as scaffold, seven novel triazole-linked compounds have been synthesized using CuAAC chemistry. The in vitro biological activity of four of the compounds on the Plasmodium falciparum chloroquine-sensitive strain NF54 was then determined. The compounds which were tested showed moderate activity with 1.45 μM as the lowest inhibitory concentration.