Katja Stangeland Håheim

• Håheim, Katja Stangeland; Sang, Liza Maeva Nguyen van & Sydnes, Magne Olav (2025). Progress in Designing Greener Antibiotics. ChemSusChem. ISSN 1864-5631. doi: 10.1002/cssc.202500788. Full text in Research Archive
• Håheim, Katja Stangeland & Sydnes, Magne Olav (2024). Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds. The chemical record. ISSN 1527-8999. 24. doi: 10.1002/tcr.202300362. Full text in Research Archive Show summary

  Cryptolepine, neocryptolepine, and isocryptolepine have remained popular synthetic targets ever since their isolation from the aqueous extracts of the West African climbing shrub Cryptolepis sanguinolenta. These natural alkaloids were found to contain significant antimalarial, antiproliferative and antimicrobial activities, making them ideal starting points for the development of novel drug candidates. As natural product synthesis is often plagued with step-heavy procedures and poor atom economy, the discovery of synthetic protocols addressing these concerns are sorely needed. In our laboratories, we have devoted our efforts into the development of regiodivergent synthesis whereby two of the indoloquinoline natural products, namely neocryptolepine and 11H-indolo[3,2-c]quinolines, could be assembled in only a few steps from a common and readily available starting material. Our synthetic endeavors to meet these goals include a cascade palladium-catalyzed Suzuki-Miyuara cross-coupling and intramolecular C−N bond formation and a photochemical nitrene insertion strategy. Furthermore, our methods also allowed for the construction of several diversely functionalized natural product derivatives which were subjected to biological evaluations.

• Håheim, Katja Stangeland; Deolka, Shubham; Fayzullin, Robert; Lund, Bjarte Aarmo; Khaskin, Eugene & Sydnes, Magne Olav (2024). 2-Pyridinyl/quinolyl-phenylamino-quinoline Complexes With CF3 and C2F5 Ligated Ni. European Journal of Inorganic Chemistry (EurJIC). ISSN 1434-1948. 27(25). doi: 10.1002/ejic.202400207. Full text in Research Archive Show summary

  A new ligand architecture based on quinoline/pyridine attached ortho to the amine functionality on an aniline, which is coupled to another quinoline unit has been prepared. Ligands <b>L1</b> and <b>L2</b> have been complexed with CF₃ and C₂F₅ ligated nickel centers. The resulting complexes have been extensively studied by NMR spectroscopy (on ¹H, ¹³C{¹H}, and ¹⁹F nuclei) and single-crystal X-ray crystallography. A poorly defined mixture of complexes obtained from <b>L1</b> and nickel bis-trifluoromethyl complex was moderately active in C−H trifluoromethylation with the Umemoto I reagent.

• Håheim, Katja Stangeland; Lund, Bjarte Aarmo & Sydnes, Magne Olav (2023). Regiodivergent Synthesis of 11H-Indolo[3,2-c]quinolines and Neocryptolepine from a Common Starting Material. European Journal of Organic Chemistry. ISSN 1434-193X. 26. doi: 10.1002/ejoc.202300137. Full text in Research Archive Show summary

  A large number of diversely functionalized analogs of the bioactive natural products neocryptolepine and isocryptolepine have been prepared from a series of 3-bromoquinoline derivatives. The neocryptolepines were obtained by a Pd⁰-catalyzed C−C bond coupling followed by C−N bond formation in yields up to 80 %, whereas the indoloquinolines were prepared by a Suzuki-Miyaura cross-coupling followed by azidation-photochemical cyclization in yields ranging from traces to 95 % yield.

• Håheim, Katja Stangeland; Albrigtsen, Marte; Helland, Kirsti; Andersen, Jeanette Hammer & Sydnes, Magne Olav (2023). Mapping the Antimicrobial Activity of Indoloquinoline and Neocryptolepine Analogues. Heterocycles. ISSN 0385-5414. 106(9), p. 1559–1569. doi: 10.3987/COM-23-14881. Full text in Research Archive
• Aquino, Gabriel Alves Souto de; Sang, Liza Maëva Nguyen van; Valery, Romane; Lanave, Maelys; Duran, Susana Estopina & Håheim, Katja Stangeland [Show all 8 contributors for this article] (2023). Photodegradable antimicrobial agents: towards structure optimization. RSC Advances. 13(42), p. 29729–29734. doi: 10.1039/d3ra05554j. Full text in Research Archive Show summary

  Antibiotic resistance continues to be an ominous threat facing human health globally and urgent action is required to limit the loss of human life. The pollution of antibiotics into the environment is one of the drivers behind the crisis. With this in mind, we have developed novel photodecomposable antimicrobial agents based on an ethanolamine scaffold, which upon photoirradiation decomposes into two major inactive fragments. Herein we describe our further work on the synthesis of novel ethanolamines with a particular focus on structure activity relationship, resulting in four new active compounds which photodecomposed into inactive fragments.

• Håheim, Katja Stangeland; Lindback, Emil; Tan, Kah Ni; Albrigtsen, Marte; Helgeland, Ida Therese Urdal & Lauga, Clemence [Show all 11 contributors for this article] (2021). Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities. Molecules. ISSN 1431-5157. 26(11). doi: 10.3390/molecules26113268. Full text in Research Archive Show summary

  A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC₅₀ = 24 nM) than Puromycin (IC₅₀ = 270 nM) and Doxorubicin (IC₅₀ = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

• Håheim, Katja Stangeland; Helgeland, Ida Therese Urdal; Lindback, Emil & Sydnes, Magne Olav (2019). Mapping the reactivity of the quinoline ring-system - Synthesis of the tetracyclic ring-system of isocryptolepine and regioisomers. Tetrahedron. ISSN 0040-4020. 75(21), p. 2949–2957. doi: 10.1016/j.tet.2019.04.026. Full text in Research Archive

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• Håheim, Katja Stangeland & Sydnes, Magne Olav (2020). Synthesis of Isocryptolepine and Regioisomers. Full text in Research Archive
• Håheim, Katja Stangeland; Helgeland, Ida Therese Urdal; Lindback, Emil & Sydnes, Magne Olav (2019). Synthesis of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers - Mapping the Reactivity of the Quinoline Ring-System. Full text in Research Archive
• Håheim, Katja Stangeland; Helgeland, Ida Therese Urdal; Lindback, Emil & Sydnes, Magne Olav (2019). Mapping the Reactivity of the Quinoline Ring-System - Synthesis of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers. Full text in Research Archive
• Sydnes, Magne Olav; Lindbäck, Emil Anders & Håheim, Katja Stangeland (2022). Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities. Universitetet i Stavanger. ISSN 9788284391083. Full text in Research Archive Show summary

  Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More-over, several functionalized derivatives of these compounds have shown great promise as antiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first developed by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further investigating alternative protocols for the construction of indoloquinolines, a regiodivergent intermediate was discovered, which allowed for the synthesis of both novel pyridophenanthridineand pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido-carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal complex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Okinawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amination. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being regioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction andintramolecular nucleophilic C-N bond formation. The scope and limitations for the novel protocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally superior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino-lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, installation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate functionalizations than the neocryptolepine approach, with no apparent trend concerning electron-withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru-bicin against human prostate cancer (IC50= 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dualanticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar-bazole was found to contain any significant activity against the evaluated Plasmodium falci-parumstrain. The antimicrobial assays revealed the importance of the inclusion of a methylgroup for activity, but not strictly in the form of an N-methyl unit, which is the general concensus in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial celllines.

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