Lise-Lotte Gundersen

• Lepsøe, Mathias Ryslett; Dalevold, Aleksander Granum & Gundersen, Lise-Lotte (2023). Selective C-7 Functionalization of Phenanthridines by Microwave-Assisted Claisen Rearrangements of 8-Allyloxyphenanthridines. ChemistryOpen. 12(7). doi: 10.1002/open.202300095. Full text in Research Archive Show summary

  Abstract Carbon‐carbon bond formation in the phenanthridine 7‐position was achieved by microwave‐assisted Claisen rearrangement of 8‐allyloxyphenanthridines. The reactions took place with excellent regioselectivity and high chemical yields. If the 7‐position was substituted, rearrangement to C‐9 took place, but the reaction occurred less readily. Rearrangements of 8‐allyloxy‐5,6‐dihydrophenanthridines (phenanthridines with a saturated B‐ring) gave a mixture of 7‐ and 9‐substituted products. The experimental results were supported by DFT (density functional theory) calculations.

• Milet-Pinheiro, Paulo; Domingos-Melo, Arthur; Olivera, Joao B.; Albuquerque, Nayara S. L.; Costa, Ana Carolina G. & Albuquerque-Lima, Sinzinando [Show all 13 contributors for this article] (2021). A Semivolatile Floral Scent Marks the Shift to a Novel Pollination System in Bromeliads. Current Biology. ISSN 0960-9822. 31(4), p. 860–868. doi: 10.1016/j.cub.2020.11.012. Full text in Research Archive Show summary

  Perfume flowers (sensu Vogel1 ) produce intense scents that function both as attractants and as the sole rewards for pollinators. The scent is collected exclusively by male euglossine bees and used during pre-mating behavior. Perfume flowers have evolved independently in 15 angiosperm families, with over 1,000 reported species across the Neotropical region. Members of Cryptanthus (Bromeliaceae) represent a puzzling exception among perfume flowers, as flowers produce nectar and do not emit a noticeable scent yet still attract euglossine males. Here, we studied the pollination ecology of Cryptanthus burle-marxii and decode the chemical communication between its flowers and euglossine males. Field observations revealed euglossine males and hummingbirds as potential pollinators. The bees always contacted anthers/stigma of C. burle-marxii while scraping the petals to obtain chemicals, whereas nectar-seeking hummingbirds normally only contacted the anthers. Based on gas chromatography-mass spectrometry/nuclear magnetic resonance analyses of flower scent samples and bioassays, we identified the diterpene copalol as the only floral scent compound triggering scent-gathering behavior in euglossine males. Unlike euglossine-bee-mediated pollination, hummingbird pollination is ancestral in the Cryptanthus clade, suggesting a case of an ongoing pollinator shift mediated by the evolution of perfume as a reward. Copalol was previously unknown as a floral scent constituent and represents the heaviest and least-volatile compound known to attract euglossine males. Our study provides the first experimental evidence that semivolatile floral compounds can mediate euglossine bee interactions. Male euglossine pollination in other plant species lacking noticeable floral scents suggests that semivolatile-mediated pollinator attraction is more widespread than currently appreciated.

• Paulsen, Britt & Gundersen, Lise-Lotte (2020). The first synthesis of (–)-agelasine F; an antimycobacterial natural product found in marine sponges in the Agelas genus. European Journal of Organic Chemistry. ISSN 1434-193X. p. 2244–2250. doi: 10.1002/ejoc.202000202. Full text in Research Archive Show summary

  (–)-Agelasine F (also known as ageline A) is a diterpene-adenine hybrid natural product isolated from marine sponges (Agelas species) and this compound is known to display cytotoxic activity against a variety of cancer cell lines as well as microorganisms. We herein report the first total synthesis of (–)-agelasine F. The commercially available and inexpensive monoterpenoid (S)-carvone was found to be a highly suitable starting material for the construction of the terpenoid part of the desired agelasine and controlling the stereochemistry of the target compound. Two alternative strategies from (S)-carvone were evaluated. Key-intermediates in the (–)-agelasine F synthesis are believed also to be valuable starting materials for total syntheses of other bioactive marine sponge metabolites. The synthetic route to (–)-agelasine F described herein is more efficient than previously published syntheses of racemic or ent-agelasine F.

• Jakubec, Martin; Totland, Christian; Rise, Frode; Chamgordani, Elahe Jafari; Paulsen, Britt & Maes, Louis [Show all 9 contributors for this article] (2020). Bioactive metabolites of marine origin have unusual effects on model membrane systems. Marine Drugs. 18(2), p. 1–11. doi: 10.3390/md18020125. Full text in Research Archive Show summary

  Marine sponges and soft corals have yielded novel compounds with antineoplastic and antimicrobial activities. Their mechanisms of action are poorly understood, and in most cases, little relevant experimental evidence is available on this topic. In the present study, we investigated whether agelasine D (compound 1) and three agelasine analogs (compound 2–4) as well as malonganenone J (compound 5), affect the physical properties of a simple lipid model system, consisting of dioleoylphospahtidylcholine and dioleoylphosphatidylethanolamine. The data indicated that all the tested compounds increased stored curvature elastic stress, and therefore, tend to deform the bilayer which occurs without a reduction in the packing stress of the hexagonal phase. Furthermore, lower concentrations (1%) appear to have a more pronounced effect than higher ones (5–10%). For compounds 4 and 5, this effect is also reflected in phospholipid headgroup mobility assessed using 31P chemical shift anisotropy (CSA) values of the lamellar phases. Among the compounds tested, compound 4 stands out with respect to its effects on the membrane model systems, which matches its efficacy against a broad spectrum of pathogens. Future work that aims to increase the pharmacological usefulness of these compounds could benefit from taking into account the compound effects on the fluid lamellar phase at low concentrations

• Gulbrandsen, Håkon Sætren; Serigstad, Halvard; Read, Matthew Lovell; Joos, Ilos & Gundersen, Lise-Lotte (2019). Formation of 8-Hydroxyphenanthridines by Microwave-Mediated IMDAF Reactions; Synthesis Directed towards Lycorine Alkaloids. European Journal of Organic Chemistry. ISSN 1434-193X. p. 6044–6052. doi: 10.1002/ejoc.201901000. Full text in Research Archive Show summary

  8‐Hydroxyphenathridines have been synthesized efficiently from N‐propargyl‐ortho‐furylanilines employing microwave‐mediated one‐pot intramolecular Diels–Alder reaction on furans (IMDAF) reaction and subsequent aromatization. The 8‐hydroxyphenathridines were also subjected to further functionalization; O‐alkylation and conversion to the corresponding triflate followed by Suzuki coupling. N‐Propargyl‐7‐furylindole and the corresponding indoline also underwent smooth IMDAF cyclization to give, after rearomatization, 7H‐pyrrolo[3,2,1‐de]phenanthridin‐9‐ol or the 4,5‐dihydro analog. These cyclization products could be further functionalized, i.e. O‐ or N‐alkylation and oxidation at C‐6. The oxidation could lead to 6‐oxo derivatives or pyrrolo[3,2,1‐de]phenanthridin‐6‐ium salts depending on the reaction conditions and structure of the substrate. The 9‐oxy‐pyrrolophenanthridines synthesized are structurally closely related to bioactive lycorine alkaloids.

• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An & Naemi, Ali-Oddin [Show all 12 contributors for this article] (2019). Synthesis and antimicrobial activities of N6-hydroxyagelasine analogs and revision of the structure of ageloximes. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 27(4), p. 620–629. doi: 10.1016/j.bmc.2019.01.002. Full text in Research Archive Show summary

  (+)-N6-Hydroxyagelasine D, the enantiomer of the proposed structure of (–)-ageloxime D, as well as N6-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N6-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N6-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5). The spectral data of N6-hydroxyagelasine D did not match those reported for ageloxime D before. Hence, a revised structure of ageloxime D was proposed. Basic hydrolysis of agelasine D gave (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, a compound with spectral data in full agreement with those reported for (–)-ageloxime D.

• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed & Gundersen, Lise-Lotte (2019). Synthesis directed towards trans-clerodanes employing an exo-selective Diels Alder reaction as a key-step. Monatshefte für Chemie. ISSN 0026-9247. 150(1), p. 49–58. doi: 10.1007/s00706-018-2277-9. Full text in Research Archive Show summary

  A potential intermediate in the synthesis of several trans-clerodane natural products has been constructed employing a Diels Alder reaction as a key-step. Two epimeric exo adducts were formed in a 4:3 ratio in an EtAlCl2 mediated cycloaddition of O-silylated 2-vinylcyclohex-2-enol and N-tigloylisoxazolidinone. Both isomers were converted to the trans-clerodane intermediate in four steps; reductive removal of the oxazolidinone, followed by O-benzylation, removal of the silyl protecting group and finally a Dess-Martin oxidation of the deprotected alcohol to the corresponding ketone. It was possible to transform both isomers from the cycloaddition into the final target, but the major isomer was converted at greater yields. An interesting discovery made during the work was that the desilylation demanded significantly different conditions depending on which isomer was deprotected. The fact that the cycloaddition not only resulted in an excellent exo selectivity, but also that the alkene to a large extent approached from the least hindered side, opens the possibility for enantioselective synthesis of the target compound from (R) or (S) diene starting materials in the future.

• Qi, Lianglin; Gundersen, Lise-Lotte & Görbitz, Carl Henrik (2018). 2-D and 3-D porous structures from tetrakis(4-thyminylmethylphenyl)methane. CrysteEngComm. 20(9), p. 1179–1184. doi: 10.1039/c8ce00078f. Full text in Research Archive
• Gulbrandsen, Håkon Sætren; Alfaro, Jessica Lizeth; Read, Matthew Lovell & Gundersen, Lise-Lotte (2017). Synthesis of Electron-Deficient Tetrahydro- and Dihydroimidazo[1,2-f]phenanthridines by Microwave-Mediated IMDAF Reactions. European Journal of Organic Chemistry. ISSN 1434-193X. 2017(16), p. 2305–2311. doi: 10.1002/ejoc.201700180. Full text in Research Archive Show summary

  N-Substituted tetrahydroimidazo[1,2-f]phenanthridines (TIPs) and dihydroimidazo[1,2-f]phenanthridines (DIPs) display a variety of interesting properties, but the structural variation in the compounds have, up till now, been only the N-substituent. TIPs and DIPs carrying electron-withdrawing substituents on the phenanthridine part of the molecule have been synthesized for the first time. A microwave-mediated one-pot intramolecular Diels-Alder reaction on furans (IMDAF) reaction and subsequent aromatization was employed as a key-step. The electron-deficient dihydrophenanthridines constructed by the IMDAF reaction were oxidized in situ by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the salts generated were reacted with benzylamine to give N-benzylated TIP compounds. These novel TIPs were remarkably stable towards air-mediated oxidation compared to TIPs not carrying electron-withdrawing substituents, and could be isolated in high yields. However, the electron-deficient TIPs were easily oxidized to the corresponding DIPs by treatment with N-bromosuccinimide.

• Hennum, Martin; Odden, Hege Hortemo & Gundersen, Lise-Lotte (2017). Rearrangement reactions leading to optically active α,α-disubstituted primary allylamines. European Journal of Organic Chemistry. ISSN 1434-193X. 2017(4), p. 846–860. doi: 10.1002/ejoc.201601446. Full text in Research Archive Show summary

  Synthetic routes to α,α-disubstituted allylamines have been examined. Racemic compounds were conveniently prepared by thermal Overman rearrangements of primary allyl alcohols with trisubstituted double bonds, but rearrangement of these substrates by the only commercially available compound known to catalyze enantioselective Overman rearrangements, the cobalt oxazoline palladacycle (R)-COP-Cl, failed. Instead optically active secondary allyl alcohols with trisubstituted double bonds, obtained by CBS-mediated reduction of the corresponding methyl ketones, were synthesized and converted to α,α-disubstituted allylamines via a thermal Overman rearrangement or an allyl cyanate to isocyanate rearrangement. High chiral transfer (90-99%) was obtained with both reaction sequences, but the chemical yields were greatly improved when the allyl cyanate to isocyanate rearrangement were employed.

• Qi, Lianglin; Gundersen, Lise-Lotte; Chamgordani, Elahe Jafari & Görbitz, Carl Henrik (2016). Watson-Crick base pairing in 9-methyladenine and ethylene-9,9′-diadenine structures with close to 70% solvent content. CrysteEngComm. 18(34), p. 6352–6357. doi: 10.1039/c6ce01159d. Full text in Research Archive
• Chamgordani, Elahe Jafari; Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2016). Selective N-7 alkylation of 3-methylhypoxanthine; the first synthesis of malonganenone J. Tetrahedron Letters. ISSN 0040-4039. 57(44), p. 4926–4929. doi: 10.1016/j.tetlet.2016.09.078. Full text in Research Archive Show summary

  3-Methylhypoxanthine has been reacted with various alkyl halides under basic conditions. Allylic and benzylic halides reacted mostly at N-7 to give dialkylated purines, however, ring-opened imidazole by-products, probably resulting from N-1 alkylation and hydrolysis of the formed salt , were often obtained in minor amounts. Less reactive halides required a larger excess, higher temperatures and longer reaction times. 3,7-Dialkylpurines were again the major products and imidazoles were formed in very minor amounts, however, considerable amount of O-alkylation also took place. The marine natural product malonganenone J was synthesized for the first time by selective N-7 alkylation of 3-methylhypoxanthine with geranylgeranyl bromide.

• Mahajan, Tushar Ravindra; Ytre-Arne, Mari; Strøm-Andersen, Pernille; Dalhus, Bjørn & Gundersen, Lise-Lotte (2015). Synthetic routes to N-9 alkylated 8-oxoguanines; weak inhibitors of the human DNA glycosylase OGG1. Molecules. ISSN 1431-5157. 20(9), p. 15944–15965. doi: 10.3390/molecules200915944. Full text in Research Archive Show summary

  The human 8-oxoguanine DNA glycosylase OGG1 is involved in base excision repair (BER); one of several DNA repair mechanisms that may counteract the effects of chemo- and radiation therapy for the treatment of cancer. We envisage that potent inhibitors of OGG1 may be found among 9-alkyl-8-oxoguanines. Thus we explored synthetic routes to 8-oxoguanines and examined these as OGG1 inhibitors. The best reaction sequence started from 6-chloroguanine and involved N-9 alkylation, C-8 bromination and finally simultaneous hydrolysis of both halides. Bromination before N-alkylation should only be considered when the N-substituent is not compatible with bromination conditions. The 8-oxoguanines were found to be weak inhibitors of OGG1. 6-Chloro-8-oxopurines, by-products in the hydrolysis of 2,6-halopurines, turned out to be slightly better inhibitors than the corresponding 8-oxoguanines

• Mahajan, Tushar Ravindra & Gundersen, Lise-Lotte (2015). Efficient functionalization of 2-amino-6-chloropurine derivatives at C-8 via 8-litiated species. Tetrahedron Letters. ISSN 0040-4039. 56(43), p. 5899–5902. doi: 10.1016/j.tetlet.2015.09.028. Full text in Research Archive Show summary

  9-Substituted 2-amino-6-chloropurines are important intermediates in the synthesis of a variety of purine and purine nucleoside derivatives, and were efficiently halogenated, alkylated and formylated at the C-8 position via lithiation of N2 mono THP protected purines. Notably, even fluoride could be introduced to the purine 8-position, but in a modest yield. Lithiation of non-protected 2-amino-6-chloropurines led to a ring-opening of the pyrimidine ring.

• Aarhus, Thomas Ihle; Fritze, Urs Fabian; Hennum, Martin & Gundersen, Lise-Lotte (2014). Sodium borohydride mediated reduction of N-Boc protected purines and applications in the synthesis of 7-alkyladenines and tetrahydro[1,4]diazepino-[1,2,3-gh]purines. Tetrahedron Letters. ISSN 0040-4039. 55(42), p. 5748–5750. doi: 10.1016/j.tetlet.2014.08.102. Full text in Research Archive Show summary

  Electron deficient purines can be reduced to 7,8-dihydropurines when treated with cheap and easy-to-handle sodium borohydride in methanol. The dihydropurine formed by reduction of tris-Boc-protected adenine is a useful intermediate in efficient syntheses of 7-alkyladenines and tetrahydro[1,4]diazepino[1,2,3-gh]purines.

• Gulbrandsen, Håkon Sætren; Hennum, Martin; Osheka, Maksim; Read, Matthew Lovell & Gundersen, Lise-Lotte (2014). Synthesis of phenanthridine derivatives functionalized in the C-ring by means of IMDAF reactions under microwave or conventional heating conditions. European Journal of Organic Chemistry. ISSN 1434-193X. p. 8182–8190. doi: 10.1002/ejoc.201403111. Full text in Research Archive Show summary

  Phenanthridines functionalized in the C-ring have been synthesized by intramolecular Diels-Alder reaction on furans (IMDAF) cyclization of ortho-furyl(alkenylamino)arenes both under microwave conditions and conventional heating. The outcome of the reactions is highly dependent on the substitution pattern both on the dienophile and the arene. 5,6-Dihydrophenanthridines, which can be easily oxidized to fully aromatic phenanthridines, are formed under microwave conditions as long as the Diels Alder adduct contains a hydrogen in the 6a-position. Aromatization of the phenanthridine C-ring does not occur when the cyclization is performed using conventional heating. The IMDAF reaction can, under these conditions, lead to Diels-Alder adducts or phenanthridines with partly saturated and functionalized C-rings, depending on the detailed structure of the starting material.

• Hennum, Martin; Fliegl, Heike; Gundersen, Lise-Lotte & Eisenstein, Odile (2014). Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines. Journal of Organic Chemistry. ISSN 0022-3263. 79(6), p. 2514–2521. doi: 10.1021/jo402802j. Full text in Research Archive Show summary

  The asymmetric nucleophilic 1,2-addition of (S)-N-benzylidene-2-methylpropane-2-sulfinamide with methylmagnesium bromide and methyllithium has been investigated using DFT(B3LYP) computations. The calculated ratio of the two diastereomers agrees with experimental observations and the factors that determine the diastereomeric ratio are discussed. The preference for the E isomer and the rapid equilibrium between the E and Z isomers of N-tert-butanesulfinyl imine are two key features for understanding the mechanism of this reaction. Methylmagnesium bromide and methyllithium have bifunctional roles, acting as both Lewis acid and nucleophile and the Lewis acid character has a determining role on the stereoselectivity of the reaction.

• Read, Matthew Lovell & Gundersen, Lise-Lotte (2013). Synthesis of Phenanthridine Derivatives by Microwave-Mediated Cyclization of o-Furyl(allylamino)arenes. Journal of Organic Chemistry. ISSN 0022-3263. 78(3), p. 1311–1316. doi: 10.1021/jo3027033. Full text in Research Archive Show summary

  A novel and efficient synthesis of phenanthridines and aza analogs is reported. The key-step is a microwave-mediated intramolecular Diels Alder cyclization of ortho-furyl(allylamino)arenes. In the presence of a catalytic amount of acid, the DA-adduct reacts further to give the dihydrophenanthridines, which easily can be oxidized to fully aromatic compounds by air in the presence of UV light or by DDQ.

• Siah, Huey San Melanie & Gundersen, Lise-Lotte (2013). Synthetic Strategies to 9-Substituted 8-Oxoadenines. Synthetic Communications. ISSN 0039-7911. 43(11), p. 1469–1476. doi: 10.1080/00397911.2011.642051. Full text in Research Archive Show summary

  Three synthetic routes to 9-substituted 8-oxoadenines have been studied: Bromination of adenine followed by N-9 alkylation/arylation and finally hydrolysis; bromination of adenine, hydrolysis and N-functionalization as the last step; N-9 alkylation of adenine, halogenation and finally hydrolysis. As long as the N-9 functional group is compatible with conditions required for introduction of the halogen, the latter strategy was found to be the most efficient. Also a strategy starting from 5-amino-4,6-dichloropyrimidine was found to be a very good alternative for synthesis of 9-substituted 8-oxoadenines.

• Lundvall, Fredrik; Kania, Jindrich & Gundersen, Lise-Lotte (2013). (E)-9-(But-2-en-1-yl)-6-chloro-9H-purine. Acta Crystallographica Section E: Structure Reports Online. E69(6), p. o849–o849. doi: 10.1107/S1600536813010416. Full text in Research Archive
• Kania, Jindrich & Gundersen, Lise-Lotte (2013). Synthesis of N-Alkenylpurines by Rearrangements of the Corresponding N-Allyl Isomers: Scopes and Limitations. European Journal of Organic Chemistry. ISSN 1434-193X. p. 2008–2019. doi: 10.1002/ejoc.201201455. Full text in Research Archive Show summary

  N-9 and N-7-alkenylpurines have been synthesized by rearrangement of the corresponding N-allyl derivatives, often in good yields and with high stereoselectivity. Base promoted and transition metal mediated rearrangements have been studied. Simple allylpurines were easily rearranged with catalytic amounts of RuClH(CO)(PPh3)3. The efficiency of base promoted rearrangement was highly dependent on the detailed structure of the starting material, but this reaction often occurred with surprisingly high Z-selectivity.

• Gundersen, Lise-Lotte (2013). Synthesis and biological activities of marine terpene-adenine hybrids and synthetic analogs. Phytochemistry Reviews. ISSN 1568-7767. 12(3), p. 467–486. doi: 10.1007/s11101-012-9236-6. Full text in Research Archive Show summary

  Marine sponges (Agelas sp., Raspailia sp.) produce bioactive metabolites, which can be regarded as hybrids between a terpenoid and an adenine derivative. Three sub classes are known: Agelasines, agelasimines and asmarines. Currently 19 agelasines or closely related structures, two agelasimines and 11 asmarines are published. The two agelasimines have been prepared by total synthesis, the same is true for some of the agelasines, but none of the asmarines have been synthesized so far. Agelasines are associated with antimicrobial and antineoplastic activities. Several analogs have been prepared, which are even more potent than the naturally occurring compounds, and interesting leads for treatment of for instance tuberculosis, Chagas disease and leishmaniasis have been identified. Also antifouling agents and biofilm inhibitors have been found among agelasines and analogs. Agelasines inhibits Na,K-ATPase and other ATPases, but how relevant this is for their mechanism of action, as antimicrobial and antineoplastic agents, are currently poorly understood. Agelasimines A and B display antineoplastic activity and they have the ability to inhibit smooth muscle contraction. Synthetic analogs with both antimicrobial and anticancer activities are known. Biological activities of asmarines are far less studied than those of agelasines and agelasimines, but some of them are claimed to be cytotoxic compounds.

• Marzouk, Victor Heshmat Rezkallah; Hennum, Martin & Gundersen, Lise-Lotte (2013). Efficient synthesis of cytotoxic pyrido[1,2-e]purines from purines employing direct C-allylation and RCM-oxidation as key steps. Tetrahedron Letters. ISSN 0040-4039. 54, p. 3437–3439. doi: 10.1016/j.tetlet.2013.04.084. Full text in Research Archive Show summary

  Cytotoxic pyrido[1,2-e]purines are readily available from 8,9-diallylpurines by ring-closing metathesis (RCM) followed by oxidation. The 8,9-diallylpurines were synthesized conveniently by addition of allylmagnesium bromide to the corresponding C-8 unsubstituted purines, followed by rearomatization of the adducts.

• Munack, Steffi; Leroux, Vincent; Roderer, Kathrin; Ökvist, Mats; Eerde, Jan Hendrik Van & Gundersen, Lise-Lotte [Show all 8 contributors for this article] (2012). When Inhibitors Do Not Inhibit: Critical Evaluation of Rational Drug Design Targeting Chorismate Mutase from Mycobacterium tuberculosis. Chemistry and Biodiversity. ISSN 1612-1872. 9(11), p. 2507–2527. doi: 10.1002/cbdv.201200322. Full text in Research Archive Show summary

  Tuberculosis (TB) is a devastating disease that claims millions of lives every year. Hindered access or non-compliance to medication, especially in developing countries, led to drug resistance, further aggravating the situation. With current standard therapies in use for over 50 years and only few new candidates in clinical trials, there is an urgent call for new TB drugs. A powerful tool for the development of new medication is structure-guided design, combined with virtual screening or docking studies. Here, we report the results of a drug-design project, which we based on a publication that claimed the structure-guided discovery of several promising and highly active inhibitors targeting the secreted chorismate mutase (*MtCM) from Mycobacterium tuberculosis. We set out to further improve on these compounds and synthesized a series of new derivatives. Thorough evaluation of these molecules in enzymatic assays revealed, to our dismay, that neither the claimed lead compounds, nor any of the synthesized derivatives, show any inhibitory effects against *MtCM.

• Read, Matthew Lovell; Krapp, Andreas; Miranda, Pedro & Gundersen, Lise-Lotte (2012). Synthesis of complex fused polycyclic heterocycles utilizing IMDAF reactions of allylamino- or allyloxy-furyl(hetero)arenes. Tetrahedron. ISSN 0040-4020. 68(7), p. 1869–1885. doi: 10.1016/j.tet.2011.12.079. Full text in Research Archive Show summary

  Arenes and heteroarenes carrying a halogen and an amino- or hydroxy group have been converted to allylamino- or allyloxy-furyl-(hetero)arenes. These compounds underwent IMDAF-reactions to give complex fused polycyclic heterocycles. The reactivity of the substrates was highly dependent on the detailed substitution pattern, however cyclizations occurred with high stereoselectivity in most cases. Experimental findings regarding reactivity and stereoselectivity were supported by calculations.

• Roggen, Heidi; Charnock, Colin; Burman, Robert; Felth, Jenny; Larsson, Rolf & Bohlin, Lars [Show all 7 contributors for this article] (2011). Antimicrobial and Antineoplastic Activities of Agelasine Analogs Modified in the Purine 2-Position. Archiv der Pharmazie. ISSN 0365-6233. 344(1), p. 50–55. doi: 10.1002/ardp.201000148. Full text in Research Archive Show summary

  Agelasines are 7,9-dialkylpurinium salts found in marine sponges (Agelas sp.), which display a variety of antimicrobial and cytotoxic effects. We have synthesized simplified agelasine analogs modified in the purine 2-position and examined their antimicrobial and anticancer activities. The compounds were screened against Staphylococcus aureus, Escherichia coli, Mycobacterium tuberculosis, Candida krusei and Candida albicans, protozoa causing tropical diseases (Plasmodium falciparum, Leishmania infantum, Trypanosoma cruzi, and Trypanosoma brucei), a panel of human cancer cell lines (U-937 GTB, RPMI 8226/s, CEM/s, and ACHN) as well as VERO and / or MRC-5 cells. The results indicate that the introduction of a methyl group in the purine 2-position is beneficial for antimycobacterial and antiprotozoal activity, and that amino groups may enhance activity against several cancer cell lines.

• Khoje, Abhijit Datta; Charnock, Colin; Wan, Baojie; Franzblau, Scott & Gundersen, Lise-Lotte (2011). Synthesis and antimycobacterial activities of non-purine analogs of 6-aryl-9-benzylpurines; imidazopyridines, pyrrolopyridines, benzimidazoles and indoles. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 19, p. 3483–3491. doi: 10.1016/j.bmc.2011.04.023. Full text in Research Archive Show summary

  6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Analogs modified in the 6-membered ring (imidazopyridines, pyrrolopyridines, benzimidazoles and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The 3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active than their 7-deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both 3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of non-replicating persistence.

• Khoje, Abhijit Datta & Gundersen, Lise-Lotte (2011). Reactivity and Regioselectivity in Stille Coupling of 3-Substituted 2,4-Dichloropyridines. Tetrahedron Letters. ISSN 0040-4039. 52(4), p. 523–525. doi: 10.1016/j.tetlet.2010.11.108. Full text in Research Archive Show summary

  The influence of substituents at C-3 of 2,4-dichloropyridines on reactivity and regioselectivity in Pd-catalyzed cross couplings is studied. As a model reaction, the (Ph3P)2PdCl2-catalyzed Stille coupling between 2-furyl(tributyl)tin and pyridines is chosen. Increased electron-withdrawing ability of a substituent at the pyridine 3-position improves the overall reactivity. Absolute selectivity for coupling at C-2 is achieved with an amino group at C-3, and the selectivity is totally reversed when the amino group is exchanged for a nitro substituent.

• Roggen, Heidi; Bohlin, Lars; Burman, Robert; Charnock, Colin; Felth, Jenny & Gorbitz, Carl Henrik [Show all 9 contributors for this article] (2011). 2-Substituted agelasine analogs: Synthesis and biological activity, and structure and reactivity of synthetic intermediates. Pure and Applied Chemistry. ISSN 0033-4545. 83(3), p. 645–653. doi: 10.1351/PAC-CON-10-09-25. Full text in Research Archive Show summary

  Abstract: 2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl- 9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1H NMR. The tautomers were identified by 1D and 2D 1H, 13C, and 15N NMR techniques, and showed significant variation both in 13C and 15N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6- amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.

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• Wilson, Steven Ray Haakon & Gundersen, Lise-Lotte (2020). Fra Tippeligaen til Champions League. Aftenposten (morgenutg. : trykt utg.). ISSN 0804-3116. Full text in Research Archive
• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An & Naemi, Ali-Oddin [Show all 12 contributors for this article] (2019). Synthesis directed towards bioactive ent-Ageloxime D and analogues. Full text in Research Archive
• Gulbrandsen, Håkon Sætren; Serigstad, Halvard; Read, Matthew Lovell & Gundersen, Lise-Lotte (2019). Synthesis of hydroxyphenanthridines and hydroxypyrrolophenanthridines through intermolecular Diels-Alder reactions on furan (IMDAF). Full text in Research Archive
• Wåhlander, Jakob Karl Kristoffer; Balcells, David; Gundersen, Lise-Lotte & Amedjkouh, Mohamed (2017). A New Phosphonamide-framework as Catalyst in Diels-Alder Reactions. Full text in Research Archive
• Chamgordani, Elahe Jafari; Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2017). Selective N-alkylation of 3-methylhypoxanthine, the first synthesis of Malonganenone J. Full text in Research Archive
• Gulbrandsen, Håkon Sætren; Alfaro, Jessica; Read, Matthew Lovell & Gundersen, Lise-Lotte (2017). Synthesis of Electron-Deficient Tetrahydroimidazophenanthridines and Dihydroimidazophenanthridines. Full text in Research Archive
• Gulbrandsen, Håkon Sætren; Alfaro, Jessica; Read, Matthew Lovell & Gundersen, Lise-Lotte (2016). Synthesis of electron-deficient tetrahydroimidazophenanthridines (TIPs). Full text in Research Archive
• Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2016). Synthesis directed towards marine natural products: Malonganenones. Full text in Research Archive
• Mahajan, Tushar Ravindra & Gundersen, Lise-Lotte (2015). Synthetic strategies for 8-oxoguanines, as potential inhibitors of DNA glycosylases. Full text in Research Archive
• Gulbrandsen, Håkon Sætren & Gundersen, Lise-Lotte (2015). Synthesis of C-ring functionalized phenanthridines employing intramolecular Diels-Alder of furan (IMDAF) as the key step. Full text in Research Archive
• Wåhlander, Jakob Karl Kristoffer; Balcells, David; Gundersen, Lise-Lotte & Amedjkouh, Mohamed (2015). Computational Study of Phosphonamides for use in Diels-Alder Reactions. Full text in Research Archive
• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed; Balcells, David & Gundersen, Lise-Lotte (2014). Synthesis directed towards asmarine fragments and development of Lewis acid Diels-Alder catalysts. Full text in Research Archive
• Hennum, Martin; Odden, Hege Hortemo & Gundersen, Lise-Lotte (2014). Nitrogen substituted quaternary stereocenter from Overman rearrangement and the allyl cyanate-to-isocyanate rearrangement. Full text in Research Archive
• Paulsen, Britt & Gundersen, Lise-Lotte (2014). Synthesis of bioactive ent-Ageloxime D, and a structurally related terpenoid. Full text in Research Archive
• Paulsen, Britt & Gundersen, Lise-Lotte (2014). Synthesis directed towards bioactive ent-Ageloxime D, and a structurally related terpenoid. Full text in Research Archive
• Gulbrandsen, Håkon Sætern; Gundersen, Lise-Lotte & Read, Matthew Lovell (2014). Construction of novel polycyclic heterocycles through intramolecular Diels-Alder reaction on furans (IMDAF). Full text in Research Archive
• Aarhus, Thomas Ihle; Fritze, Urs Fabian; Hennum, Martin & Gundersen, Lise-Lotte (2014). Synthetic Routes to Tetrahydrodiazepinopurines - The Heterocyclic Ring System Found in Asmarines. Full text in Research Archive
• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed; Balcells, David & Gundersen, Lise-Lotte (2014). Synthesis of Asmarine Fragments and Development of Lewis Acid Diels-Alder Catalysts. Full text in Research Archive
• Hennum, Martin; Fliegl, Heike; Gundersen, Lise-Lotte & Eisenstein, Odile (2014). Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines. Full text in Research Archive
• Gundersen, Lise-Lotte (2013). Cyclization reactions in construction of heterocyclic systems. Full text in Research Archive
• Hennum, Martin; Eisenstein, Odile; Fliegl, Heike & Gundersen, Lise-Lotte (2013). Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines. Full text in Research Archive
• Paulsen, Britt & Gundersen, Lise-Lotte (2013). Synthesis of bioactive ent-ageloxime D. Full text in Research Archive
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2013). Møysommelig medisinjakt. [Internet]. www.forskning.no. Full text in Research Archive
• Gundersen, Lise-Lotte (2013). Non-purine Analogs of Antimycobacterial 6-Aryl-9-benzylpurines: Synthesis, Biological Activities and Spin-off Projects. Full text in Research Archive
• Miller, Charlotte Marie; Benneche, Tore & Gundersen, Lise-Lotte (2013). Total synthesis of the prostanoids Clavulolactone II, Clavulolactone III and Carijenone. Full text in Research Archive
• Siah, Huey-San Melanie & Gundersen, Lise-Lotte (2013). Strategies to 9-Substituted-8-oxoadenines. 28. Organisk-kjemisk vintermøte. Full text in Research Archive
• Mahajan, Tushar Ravindra & Gundersen, Lise-Lotte (2013). Design, synthesis and biological evaluation of 8-oxoguanine derivatives as potential inhibitiors of DNA glycosylases - possible adjuvants in cancer treatment. Full text in Research Archive
• Mahajan, Tushar Ravindra & Gundersen, Lise-Lotte (2013). Design, synthesis and biological evaluation of 8-oxoguanine derivatives as potential inhibitiors of DNA glycosylases - possible adjuvants in cancer treatment. Full text in Research Archive
• Paulsen, Britt & Gundersen, Lise-Lotte (2013). Synthesis of Bioactive Agelasines, Analogs and Structurally Related Terpenoids. Full text in Research Archive
• Kania, Jindrich & Gundersen, Lise-Lotte (2012). Synthetic studies directed towards Asmarines. Full text in Research Archive
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2012). Her starter jakten på en ny medisin. [Internet]. Teknisk ukeblad. Full text in Research Archive
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2012). Møysommelig medisinjakt. [Internet]. www.forskningsradet.no. Full text in Research Archive
• Hennum, Martin & Gundersen, Lise-Lotte (2012). Methodology towards the total synthesis of asmarines. Full text in Research Archive
• Kania, Jindrich & Gundersen, Lise-Lotte (2012). Methods for isomerisation of the double bond in N-allyl purines. Organisk-kjemisk vintermøte. Full text in Research Archive
• Read, Matthew Lovell & Gundersen, Lise-Lotte (2012). Synthesis of tricyclic aromatic compounds by intramolecular Diels Alder reaction on furanes (IMDAF) and water elimination under microwave conditions followed by rearomatization. Full text in Research Archive
• Hennum, Martin; Odden, Hege Hortemo; Gundersen, Lise-Lotte & Hansen, Tore (2012). Methodology towards the total synthesis of asmarines. Full text in Research Archive
• Gundersen, Lise-Lotte; Kania, Jindrich; Odden, Hege Hortemo; Proszenyak, Agnes & Vik, Anders (2011). Synthesis directed towards Agelasines and Asmarines; Marine Antibiotics. Full text in Research Archive
• Gundersen, Lise-Lotte (2011). Synthesis directed towards bioactive compounds. Full text in Research Archive
• Gundersen, Lise-Lotte (2011). Organisk kjemi i utvikling av nye medisiner. Full text in Research Archive
• Gundersen, Lise-Lotte (2011). Synthesis directed towards Agelasines and Asmarines: Marine Antibiotics. Full text in Research Archive
• Gundersen, Lise-Lotte; Brændvang, Morten; Khoje, Abhijit Datta; Read, Matthew Lovell & Miranda, Pedro (2011). Non-purine Analogs of Antimycobacterial 6-Aryl-9-benzylpurines: Synthesis and Biological Activities. Full text in Research Archive
• Kania, Jindrich & Gundersen, Lise-Lotte (2011). Double bond migration in N-allyl purines, scope and limitation. Full text in Research Archive
• Kildahl-Andersen, Geir; Kulendrn, Aisveraya; Orji, Placid N.; Müller, Christa & Gundersen, Lise-Lotte (2011). Synthesis, biological evaluation and docking studies of selective, purine.based adenosine receptor antagonists. Full text in Research Archive
• Khoje, Abhijit Datta; Gundersen, Lise-Lotte; Charnock, Colin; Wan, Baojie & Franzblau, Scott (2011). Deaza analogs of antimycobacterial 6-aryl-9-benzyl purines: Imidazopyridines, Pyrrolopyridines and benzimidazoles. Full text in Research Archive
• Munack, Steffi; Leroux, Vincent; Roderer, Katrin; Ökvist, Mats; Bryntesen, Tina & Thiemicke, Alexander [Show all 10 contributors for this article] (2011). A structure-guided approach to new tuberculosis drugs – potential inhibiyors of Mycobacterium tuberculosis chorismate mutase. Full text in Research Archive
• Siah, Huey San Melanie; Gundersen, Lise-Lotte & Gorbitz, Carl Henrik (2011). NMR and X-ray structural studies of 3-benzyl-8-bromoadenine. Full text in Research Archive
• Odden, Hege Hortemo & Gundersen, Lise-Lotte (2011). Synthesis of allylic amines as building blocks for asmarine analogs. Full text in Research Archive
• Lim, Fiona S. P.; Siah, Huey San Melanie & Gundersen, Lise-Lotte (2011). Synthesis of 8-bromo-9-substituted purines. Full text in Research Archive
• Read, Matthew Lovell; Krapp, Andreas & Gundersen, Lise-Lotte (2011). Intramolecular Diels-Alder reaction on furan (IMDAF), resulting in new complex multicyclic fused ring systems. Full text in Research Archive
• Ali, Mohamed Ahmed & Gundersen, Lise-Lotte (2024). Synthesis directed towards antimicrobial phenanthridines; Azaphenanthridines. Universitetet i Oslo. Full text in Research Archive
• Lepsøe, Mathias Ryslett & Gundersen, Lise-Lotte (2022). ortho-Functionalization of 8-hydroxyphenanthridines. Universitetet i Oslo. Full text in Research Archive
• Dalevold, Aleksander Granum & Gundersen, Lise-Lotte (2021). Synthesis directed towards 8-hydroxyphenanthridines functionalized in the C-ring. Universitetet i Oslo. Full text in Research Archive
• Gulbrandsen, Håkon Sætren & Gundersen, Lise-Lotte (2020). Synthesis of Phenanthridine-Containing Polycyclic Ring Systems through Intramolecular Diels-Alder Reaction on Furan (IMDAF). Universitetet i Oslo. Full text in Research Archive Show summary

  The work described in this thesis focused on developing a method to synthesise a variety of organic molecules with imidazophenanthridine or pyrrolophenanthridine ring structures. These are complex structures with previously reported activities against certain cancer cell lines, and as acetylcholinesterase inhibitors, among else. Acetylcholinesterase inhibitors are potentially useful as drugs for the treatment of Alzheimer’s disease. This newly developed route to imidazophenanthridines allow for a substitution pattern not previously reported for similar structures, namely the inclusion of electron-withdrawing groups in the phenanthridine A-ring. These types of imidazophenanthridines are relatively unexplored territory, so the synthesis route’s potential to produce a variety of different substitution patterns is important. Some of the products that were tested for biological activities displayed significant activity against certain protozoa parasites responsible for tropical diseases. In the method developed towards pyrrolophenanthridines, an elegant solution was found to introduce one of the two characteristic hydroxyl groups observed in naturally occurring analogs. It was also discovered that some of the synthesised compounds were sensitive towards oxidation, which can be exploited in further studies to introduce additional functionality.

• Paulsen, Britt & Gundersen, Lise-Lotte (2020). Total Synthesis of Agelasine F and Synthesis towards ent-Ageloxime D: Two Natural Products with Interesting Biological Activities. Universitetet i Oslo. Full text in Research Archive Show summary

  The work described in this thesis has focused on total synthesis directed towards two different classes of secondary metabolites isolated from the Agelas sponge, ageloxime D and analogs, and agelasine F. Ageloximes were reported to be 7,9-dialkylpurinium salts carrying a diterpenoid side chain in the 7-position and a hydroxylamine substituent in the 6-position. The enantiomer of the reported structure of ageloxime D was the target compound, along with two different analogs carrying either a geranyl or geranylgeranyl side chain. The enantiomer of the naturally occurring ageloxime D was chosen as the target compound because the enantiomer of the side chain of ageloxime D can be bought. Starting from (+)-manool, the sidechain was converted into (+)-copalol in four steps. There are no reported syntheses of ageloximes, and therefore a synthetic strategy was established. Starting from 9-methylated 6-chloropurine, a method for introducing a hydroxylamine in high yields had to be developed. As the selectivity of the alkylation of the sidechain at N 7 was rather poor, it was necessary to introduce a removable directing group on the hydroxylamine. Tert -butyldimethylsilyl was the preferred choice, as it is sterically demanding and possible to remove under mild conditions. The selectivity of the alkylation at N 7 was improved dramatically with the directing group. The removal of the directing group was eventually performed with ammonium fluoride, yielding ent -ageloxime D and analogs. The compounds were tested for biological activity and ent - ageloxime D and geranylgeranyl-ageloxime displayed high activity against the protozoa causing leishmaniasis and Chagas disease in addition to Mycobacterium tuberculosis. Agelasines are also 7,9-dialkylpurinium salts carrying a diterpenoid side chain in the adenine 7-position. Agelasine F was synthesized starting from ( S )-carvone, and the synthesis of the side chain focused on avoiding and improving some key steps was the main goal. The key steps were the introduction of the chloromethyl phenyl sulfide with the right stereochemistry, including the formation of the silyl enol ether and the avoidance of the expensive alternative starting material, ( S )-pulegone. This compound has shown interesting activity against some drug resistant strains of M. tuberculosis in vitro and also inhibition of Na,K-ATPase

• Bjerkmann, Marcel & Gundersen, Lise-Lotte (2019). Synthesis of Novel Phenanthridin-8-ol Derivatives Functionalized in the A- and C-rings by Means of a Microwave-mediated Intramolecular Diels-Alder Cycloaddition on Furan (IMDAF) Reaction. Universitetet i Oslo. Full text in Research Archive
• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed & Gundersen, Lise-Lotte (2018). Diels-Alder reactions in synthesis and method development. University of Oslo. Full text in Research Archive Show summary

  This thesis has got two parts within the common theme of Diels-Alder reactions. One part starts with the group of natural products called asmarines. These compounds, which were found in the red sea sponges, were believed to have anti-cancer properties. However a synthetic pathway to these compounds does as of yet not exist. A potential synthetic pathway for a fragment of the asmarines was devised, using a Diels-Alder reaction in a crucial step. The other part starts with thioureas, a class of compounds that act as Diels-Alder catalysts by way of hydrogen bond activation of and α,β-unsaturated carbonyl compound. A new, but similar, phosphordiamide based framework that was hypothesized to act in a similar manner to the thioureas. It was thought that a functioning phosphordiamide catalyst could be used in the crucial Diels-Alder reaction of the asmarine fragment. A more in detail description is found in Chapter 1. In Chapter 2 the initial attempts at producing a functional phosphordiamide catalyst are presented. A few simple catalysts are produced and evaluated using several different systems. The compounds are however unsuccessful as Diels-Alder catalysts. Further studies of phosphordiamides can be found in Chapter 3 which deals with a computational study a new set of phosphordiamide catalysts, with more successful results. The Chapter 4 deals with the previously discussed synthetic pathway of an asmarine fragment. The idea of using a phosphordiamide as a catalyst was discarded in favor of a Lewis acid catalyst. Though the synthesis of the fragment was not complete, the main Diels-Alder step was eventually overcome and several more steps were completed with good yields. The final Chapter 5 describes a possible continuation to both projects.

• Serigstad, Halvard & Gundersen, Lise-Lotte (2018). Synthesis of 8-hydroxyphenanthridines employing Intramolecular Diels-Alder of Furan as the key step. Universitetet i Oslo. Full text in Research Archive Show summary

  Abstract A synthetic strategy towards 8-hydroxyphenanthridines (6) was previously developed in our group, where intramolecular Diels-Alder of furan (IMDAF) was the key step. This was a continuation of a previous work as well. This strategy turned out to be not very efficient and a new and more robust strategy was planned out. The new strategy doesn’t involve diastereomers and is focused on obtaining 8- hydroxyphenanthridines in high yields, which later on can be explored for a fully functionalized ring c.

• Endsjø, Janine Moløkken Munthe & Gundersen, Lise-Lotte (2017). Synthesis Directed towards Potential hOGG1 Inhibitors. Universitetet i Oslo. Full text in Research Archive
• Mahajan, Tushar Ravindra; Gundersen, Lise-Lotte & Dalhus, Bjørn (2016). Design, synthesis and biological evaluation of 8-oxoguanine derivatives as DNA glycosylase inhibitors and efficient functionalization of 2-amino-6-chloropurines at C-8 via lithiated species. Universitetet i Oslo. Full text in Research Archive Show summary

  Resistance to chemotherapy and/or radiotherapy limits the effectiveness of cancer treatment. One factor that can contribute to resistance is the process of DNA repair. Among the different DNA repair pathways, the base excision repair (BER) is a multi-step, multi-enzyme pathway that is able to recognize and correct small changes in native nucleobases of the DNA. 8-Oxoguanine DNA glycosylase (OGG1) is one of the enzymes in this pathway which removes the oxidized guanine lesion from DNA. Inhibitors of OGG1 might improve the outcome of certain cancer treatments by temporarily inhibiting the BER pathway in tumour cells and may act as adjuvants in cancer treatment. It was envisaged that 8-oxoguanine derivatives may act as OGG1 inhibitors as they contain the signature scaffold of oxidized native guanine. The present thesis is focused on the design and synthesis of 8-oxoguanine derivatives and their biological evaluation as DNA glycosylase inhibitors. Suitable synthetic strategies were developed to obtain 8-oxoguanine derivatives with various N-9 substituents. The 8-oxoguanines were efficiently synthesized using a threestep strategy: N-alkylation of guanine precursors at N-9, C-8 bromination and hydrolytic cleavage of bromide. Purines are known to give varying ratio of N-9/ N-7 regioisomers depending on the nature of substituents and methods of N-alkylation. Two guanine precursors were alkylated by different N-alkylation strategies viz. base induced alkylation, Mitsunobu coupling, and palladium catalyzed allylation. The regioisomeric outcome of these strategies was studied. In the next step, N-9-alkylated purines were brominated either by direct bromination or by a lithiation/halogenation protocol depending on the nature of the substituent and its compatibility with brominating conditions. Finally, the brominated derivatives were hydrolyzed to the target compounds, 8-oxoguanine derivatives, during which the partially hydrolyzed 6-chloro-8-oxoguanine derivatives were also isolated. The 8-oxoguanine derivatives and 6-chloro-8-oxoguanine derivatives were evaluated for their ability to inhibit OGG1 using an OGG1 assay. The synthesized compounds showed a moderate inhibitory effect on OGG1. During the course of the study, 9-alkylated 2-amino-6-chloropurine in the presence of a strong base such as LDA, gave the ring-opened products. 9-Alkylated 2-amino-6- chloropurines were functionalized at C-8 via lithiation/halogenation protocol using appropriately protected 2-amino-6-chloropurine. The scope of the C-8 lithiation was evaluated using various electrophiles. The findings of the work will be useful in choosing efficient synthetic strategies for new derivatives of 8-oxoguanines and 6-chloro-8-oxoguanines for future development of DNA glycosylase inhibitors.

• Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2016). Synthesis directed towards marine natural products. Malonganenone. Universitetet i Oslo. Full text in Research Archive
• Mai, Ngan Thi Kim & Gundersen, Lise-Lotte (2015). C-C Bond formation in the purine 8-position by addition of allylmetals. Universitetet i Oslo. Full text in Research Archive Show summary

  8-Substituted purines have been extensively studied as for example anticancer or antiviral drugs. C-C Bond formation at the purine 8-position has been most commonly done via 8-halopurines, e.g. Pd-catalyzed coupling reactions. Meanwhile, direct conversion of purines not substituted at C-8 to 8-alkylpurines seems to be promising but there are few reports in the literature. In this thesis, addition of an allylmetallic reagent to 8-unsustituted purines followed by oxidation of the adduct to form 8-allylated purines will be discussed.

• Qi, Lianglin; Görbitz, Carl Henrik & Gundersen, Lise-Lotte (2015). Supramolecular synthesis of porous crystalline networks from DNA-based building units. Universitetet i Oslo. Full text in Research Archive
• Aarhus, Thomas Ihle & Gundersen, Lise-Lotte (2014). Synthetic Routes to Tetrahydrodiazepinopurines - The Heterocyclic Ring System Found in Asmarines. Universitetet i Oslo. Full text in Research Archive
• Gulbrandsen, Håkon Sætren & Gundersen, Lise-Lotte (2014). Synthesis of C-Ring Functionalized Phenanthridines employing Intramolecular Diels-Alder of Furan (IMDAF) as the Key Step. Universitetet i Oslo. Full text in Research Archive Show summary

  A synthetic strategy towards the (aza)phenanthridine ring-system (3) employing an intramolecular Diels-Alder of furan (IMDAF) as the key step, has previously been developed in our research group (Scheme 1). The exploration of this synthetic pathway has until now been focused on substitution in the phenanthridine A-ring. Herein is described the synthesis of (partly reduced) phenanthridines functionalized in the C-ring by employing a substituted allylic moiety, and by selective ringopening of the intramolecular Diels-Alder adduct 7 (Scheme 2).

• Kania, Jindrich & Gundersen, Lise-Lotte (2013). Synthetic Studies directed towards Asmarines. Universitetet i Oslo. Full text in Research Archive Show summary

  The present thesis is focused on the design of synthetic routes towards asmarine analogues. Asmarines are marine natural products isolated from the sponges Raspalia sp. The asmarine molecule contains a seven-membered ring fused with a purine core. This tetrahydrodiazepinopurine moiety has previously been constructed for example by ringclosing metathesis (RCM). We were focused on developing this RCM reaction pathway further, in order to introduce a chiral centre to the 7-membered ring. The attempts to employ chiral allylic amines in the strategy were not successful. However, we managed to achieve the synthesis of the seven-membered ring by a novel synthetic approach employing Ru-catalysed double bond migration and Cu-catalysed C-N coupling. Thus, a new method for double bond migration of N-allyl purines was successfully developed, involving the substrate 7-allyl-6-iodo-7H-purine and the catalyst RuClH(CO)(PPh3)3. Furthermore, the possibilities of C-N bond formation between tert-butyl allylcarbamate and 7-alkylated 6-halopurines were investigated. Suitable conditions for the coupling were determined using the Goldberg reaction and 6-iodo-7-(prop-1-en-1-yl)-7Hpurine was successfully coupled with tert-butyl allylcarbamate, giving tert-butyl allyl(7-(prop-1-en-1-yl)-7H-purin-6-yl)carbamate. Finally, the RCM with this intermediate led to the previously known 7,8,9,10-tetrahydro-[1,4]diazepino[1,2,3-gh]purine. In addition, attention is paid to the synthesis and rearrangement of N-allyl to Npropenyl purines. There are very few convenient routes to N-alkenylpurines in general. Therefore, we have carried out a study on the isomerisation of 9-allyl- and 7-allylpurines. Various N-allyl purines were prepared, and base- or transition metal complex promoted isomerisations were explored. Subsequently, this study was extended for substrates bearing additional substitution on the allyl chain. Scope and limitation of the double bond migration methodologies and E/Z selectivity is discussed.

• Read, Matthew Lovell & Gundersen, Lise-Lotte (2013). Synthetic Studies Directed Towards Antimycobacterial Pyrimidines, Resulting in the Investigation of the IMDAF Reaction for the Preparation of Substituted Polycyclic Compounds. Universitetet i Oslo. Full text in Research Archive
• Marzouk, Victor Heshmat Rezkallah & Gundersen, Lise-Lotte (2013). Synthesis directed towards tricyclic heterocycles with DNA intercalating properties. Universitetet i Oslo. Full text in Research Archive Show summary

  4-Substituted pyrido[1,2-e]purines as anticancer agents have the ability to intercalate with DNA molecules and display improved cytotoxic activities especially towards the resistant cancer cell lines (MCF7R). These compounds were originally synthesized from imidazopyridines via poor yielding synthetic routes. Herein we discuss the development of more efficient strategies towards pyrido[1,2-e]purines. Since pyrido[1,2-e]purines vary mostly by their 4-substituent, we also wanted to develop more efficient strategy where the 4-substituent can be introduced in the last step.

• Munack, Steffi; Krengel, Ute & Gundersen, Lise-Lotte (2013). Enzymes of the shikimate pathway of Mycobacterium tuberculosis – Functional Studies and Drug Design. Universitetet i Oslo. Full text in Research Archive
• Odden, Hege Hortemo & Gundersen, Lise-Lotte (2011). Synthesis of alfa-functionalized allylamines employing the Overman rearrangement. Universitetet i Oslo. Full text in Research Archive
• Gundersen, Lise-Lotte & Siah, Huey-San Melanie (2011). Synthesis of 9-Substituted-8-oxoadenines as Potential Inhibitors of DNA Repair Enzymes in Cancer Therapy. Universitetet i Oslo. Full text in Research Archive
• Lim, Fiona Shiao Ping & Gundersen, Lise-Lotte (2011). Functionalization of the Purine 8-Position via 8-Purinyl anions; Scopes and Limitations with Respect to Substituents at N9. Universitetet i Oslo. Full text in Research Archive Show summary

  The present thesis is focused on the methodology of lithiation-halogenation of 6-chloro-9-substituted purines and 9-substituted adenines via 8-purinyl anions. As an extension of this work, lithiation-halogenation of 7-allyl-6-chloro-7H-purine was also investigated.

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