Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

• Main Author: Håheim, Katja S.
• Other Authors: Sydnes, Magne Olav, Lindbäck, Emil
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: University of Stavanger, Norway 2022
• Subjects: kjemi; malaria; VDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Biokjemi: 476; VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440; Helgeland
• Online Access: https://hdl.handle.net/11250/3011932

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 ...