Lise-Lotte Gundersen

• Gulbrandsen, Håkon Sætren; Serigstad, Halvard; Read, Matthew Lovell; Joos, Ilah & 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.  (35), s 6044- 6052 . doi: 10.1002/ejoc.201901000 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; Scheie, Anne Aamdal; Simm, Roger; Ma, Rui; Wan, Baojie; Franzblau, Scott & Gundersen, Lise-Lotte (2019). Synthesis and antimicrobial activities of N6-hydroxyagelasine analogs and revision of the structure of ageloximes. Bioorganic & Medicinal Chemistry.  ISSN 0968-0896.  27(4), s 620- 629 . doi: 10.1016/j.bmc.2019.01.002 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), s 49- 58 . doi: 10.1007/s00706-018-2277-9 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.  ISSN 1466-8033.  20(9), s 1179- 1184 . doi: 10.1039/c8ce00078f
• 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), s 2305- 2311 . doi: 10.1002/ejoc.201700180 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), s 846- 860 . doi: 10.1002/ejoc.201601446 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.

• 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), s 4926- 4929 . doi: 10.1016/j.tetlet.2016.09.078 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.

• 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.  ISSN 1466-8033.  18(34), s 6352- 6357 . doi: 10.1039/c6ce01159d
• 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), s 5899- 5902 . doi: 10.1016/j.tetlet.2015.09.028 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.

• 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 1420-3049.  20(9), s 15944- 15965 . doi: 10.3390/molecules200915944 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

• 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), s 5748- 5750 . doi: 10.1016/j.tetlet.2014.08.102 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.  (36), s 8182- 8190 . doi: 10.1002/ejoc.201403111 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), s 2514- 2521 . doi: 10.1021/jo402802j 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.

• Gundersen, Lise-Lotte (2013). Synthesis and biological activities of marine terpene-adenine hybrids and synthetic analogs. Phytochemistry Reviews.  ISSN 1568-7767.  12(3), s 467- 486 . doi: 10.1007/s11101-012-9236-6 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.

• 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.  (10), s 2008- 2019 . doi: 10.1002/ejoc.201201455 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.

• 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.  ISSN 1600-5368.  E69(6), s o849 . doi: 10.1107/S1600536813010416
• 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, s 3437- 3439 . doi: 10.1016/j.tetlet.2013.04.084 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.

• 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), s 1311- 1316 . doi: 10.1021/jo3027033 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), s 1469- 1476 . doi: 10.1080/00397911.2011.642051 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.

• Munack, Steffi; Leroux, Vincent; Roderer, Kathrin; Ökvist, Mats; Van Eerde, Jan Hendrik; Gundersen, Lise-Lotte; Krengel, Ute & Kast, Peter (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), s 2507- 2527 . doi: 10.1002/cbdv.201200322 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), s 1869- 1885 . doi: 10.1016/j.tet.2011.12.079 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.

• Gundersen, Lise-Lotte; Gorbitz, Carl Henrik; Neier, Liina; Roggen, Heidi & Tamm, Toomas (2011). Calculated tautomeric equilibria and X-ray structures of 2-substituted N-methoxy-9-methyl-9H-purin-6-amines. Theoretical Chemistry accounts.  ISSN 1432-881X.  129(3-5), s 349- 358 . doi: 10.1007/s00214-010-0850-3
• 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, s 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), s 523- 525 . doi: 10.1016/j.tetlet.2010.11.108 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; Larsson, Rolf; Tamm, Toomas & Gundersen, Lise-Lotte (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), s 645- 653 . doi: 10.1351/PAC-CON-10-09-25 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.

• Roggen, Heidi; Charnock, Colin; Burman, Robert; Felth, Jenny; Larsson, Rolf; Bohlin, Lars & Gundersen, Lise-Lotte (2011). Antimicrobial and Antineoplastic Activities of Agelasine Analogs Modified in the Purine 2-Position. Archiv der Pharmazie.  ISSN 0365-6233.  344(1), s 50- 55 . doi: 10.1002/ardp.201000148 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.

• Siah, Huey San Melanie; Gorbitz, Carl Henrik & Gundersen, Lise-Lotte (2011). NMR and X-ray structural studies on 3-benzyl-8-bromoadenine. Journal of Heterocyclic Chemistry.  ISSN 0022-152X.  48, s 1375- 1378 . doi: 10.1002/jhet733 Show summary

  8-Bromoadenine was benzylated in the presence of base to give a mixture of two regioisomers. One was easily recognized as 9-benzyl-8-bromoadenine, but the other structure could not be determined with absolute certainty by NMR. X-ray crystallography was therefore employed to prove that the benzyl group was attached to N-3. Furthermore, it is shown that the 3-benzyl adenine derivative exists as the amine tautomer both in the crystalline state as well as in solution (DMSO-d6), with restricted rotation around the N6-C6 bond.

• Gamadeku, T & Gundersen, Lise-Lotte (2010). Synthesis of 8-Bromo-N-benzylpurines via 8-Lithiated Purines: Scope and Limitations. Synthetic Communications.  ISSN 0039-7911.  40(18), s 2723- 2735 . doi: 10.1080/00397910903318708 Show summary

  9-Benzylpurines have been lithiated in the 8-position and subsequently brominated when trapped with BrCCl2CCl2Br. The 8-bromopurines were isolated in high yields when the benzyl group carried an alkoxy or alkyl group in the ortho or para position. Without these substituents, the conversion was generally lower and formation of 8,8’-purinyl dimers were observed. There was also evidence of debenzylation in some instances. Bromination of 7-benzylpurines employing the same set of reaction conditions has also been achieved.

• Khoje, Abhijit Datta; Kulendrn, Aisvareya; Charnock, Colin; Wan, Baojie; Franzblau, Scott & Gundersen, Lise-Lotte (2010). Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring. Bioorganic & Medicinal Chemistry.  ISSN 0968-0896.  18(20), s 7274- 7282 . doi: 10.1016/j.bmc.2010.08.016 Show summary

  Purine analogs modified in the 5-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H37Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.

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• 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).
• Paulsen, Britt; Fredriksen, Kim Alex; Petersen, Dirk; Maes, Louis; Matheeussen, An; Naemi, Ali-Oddin; Scheie, Anne Aamdal; Simm, Roger; Ma, Rui; Wan, Baojie; Franzblau, Scott & Gundersen, Lise-Lotte (2019). Synthesis directed towards bioactive ent-Ageloxime D and analogues.
• Serigstad, Halvard & Gundersen, Lise-Lotte (2018). Synthesis of 8-hydroxyphenanthridines employing Intramolecular Diels-Alder of Furan as the key step. 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.

• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed & Gundersen, Lise-Lotte (2018). Diels-Alder reactions in synthesis and method development. Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo.. 2018. 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.

• Wåhlander, Jakob Karl Kristoffer; Balcells, David; Gundersen, Lise-Lotte & Amedjkouh, Mohamed (2017). A New Phosphonamide-framework as Catalyst in Diels-Alder Reactions.
• Chamgordani, Elahe Jafari; Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2017). Selective N-alkylation of 3-methylhypoxanthine, the first synthesis of Malonganenone J..
• Endsjø, Janine Moløkken Munthe & Gundersen, Lise-Lotte (2017). Synthesis Directed towards Potential hOGG1 Inhibitors.
• Gulbrandsen, Håkon Sætren; Alfaro, Jessica; Read, Matthew Lovell & Gundersen, Lise-Lotte (2017). Synthesis of Electron-Deficient Tetrahydroimidazophenanthridines and Dihydroimidazophenanthridines.
• Gulbrandsen, Håkon Sætren; Alfaro, Jessica; Read, Matthew Lovell & Gundersen, Lise-Lotte (2016). Synthesis of electron-deficient tetrahydroimidazophenanthridines (TIPs)..
• 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. Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo.. 1755. 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.
• Paulsen, Jan Christian Holgado & Gundersen, Lise-Lotte (2016). Synthesis directed towards marine natural products: Malonganenones..
• Wåhlander, Jakob Karl Kristoffer; Balcells, David; Gundersen, Lise-Lotte & Amedjkouh, Mohamed (2015). Computational Study of Phosphonamides for use in Diels-Alder Reactions.
• Gulbrandsen, Håkon Sætren & Gundersen, Lise-Lotte (2015). Synthesis of C-ring functionalized phenanthridines employing intramolecular Diels-Alder of furan (IMDAF) as the key step.
• Mahajan, Tushar Ravindra & Gundersen, Lise-Lotte (2015). Synthetic strategies for 8-oxoguanines, as potential inhibitors of DNA glycosylases.
• Mai, Ngan Thi Kim & Gundersen, Lise-Lotte (2015). C-C Bond Formation in the Purine 8-Position by Addition of Allylmetals. 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.
• Hennum, Martin; Fliegl, Heike; Gundersen, Lise-Lotte & Eisenstein, Odile (2014). Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines.
• 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.
• Wåhlander, Jakob Karl Kristoffer; Amedjkouh, Mohamed; Balcells, David & Gundersen, Lise-Lotte (2014). Synthesis of Asmarine Fragments and Development of Lewis Acid Diels-Alder Catalysts.
• Aarhus, Thomas Ihle; Fritze, Urs Fabian; Hennum, Martin & Gundersen, Lise-Lotte (2014). Synthetic Routes to Tetrahydrodiazepinopurines - The Heterocyclic Ring System Found in Asmarines.
• Aarhus, Thomas Ihle & Gundersen, Lise-Lotte (2014). Synthetic Routes to Tetrahydrodiazepinopurines - The Heterocyclic Ring System Found in Asmarines.
• Gulbrandsen, Håkon Sætern; Gundersen, Lise-Lotte & Read, Matthew Lovell (2014). Construction of novel polycyclic heterocycles through intramolecular Diels-Alder reaction on furans (IMDAF).
• Gulbrandsen, Håkon Sætren & Gundersen, Lise-Lotte (2014). Synthesis of C-Ring Functionalized Phenanthridines employing Intramolecular Diels-Alder of Furan (IMDAF) as the Key Step.
• Hennum, Martin; Odden, Hege Hortemo & Gundersen, Lise-Lotte (2014). Nitrogen substituted quaternary stereocenter from Overman rearrangement and the allyl cyanate-to-isocyanate rearrangement.
• Paulsen, Britt & Gundersen, Lise-Lotte (2014). Synthesis directed towards bioactive ent-Ageloxime D, and a structurally related terpenoid.
• Paulsen, Britt & Gundersen, Lise-Lotte (2014). Synthesis of bioactive ent-Ageloxime D, and a structurally related terpenoid.
• Hennum, Martin; Eisenstein, Odile; Fliegl, Heike & Gundersen, Lise-Lotte (2013). Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines.
• Gundersen, Lise-Lotte (2013). Cyclization reactions in construction of heterocyclic systems.
• Gundersen, Lise-Lotte (2013). Non-purine Analogs of Antimycobacterial 6-Aryl-9-benzylpurines: Synthesis, Biological Activities and Spin-off Projects.
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2013, 23. februar). Møysommelig medisinjakt. [Internett].  www.forskning.no.
• Kania, Jindrich & Gundersen, Lise-Lotte (2013). Synthetic studies directed towards asmarines. Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo.. 1342.
• 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.
• 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.
• Marzouk, Victor Heshmat Rezkallah & Gundersen, Lise-Lotte (2013). Synthesis directed towards tricyclic heterocycles with DNA intercalating properties. 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.

• Miller, Charlotte Marie; Benneche, Tore & Gundersen, Lise-Lotte (2013). Total synthesis of the prostanoids Clavulolactone II, Clavulolactone III and Carijenone.
• Munack, Steffi; Krengel, Ute & Gundersen, Lise-Lotte (2013). Enzymes of the shikimate pathway of Mycobacterium tuberculosis – Functional Studies and Drug Design.
• Paulsen, Britt & Gundersen, Lise-Lotte (2013). Synthesis of Bioactive Agelasines, Analogs and Structurally Related Terpenoids.
• Paulsen, Britt & Gundersen, Lise-Lotte (2013). Synthesis of bioactive ent-ageloxime D.
• 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. Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo.. 1421.
• Siah, Huey-San Melanie & Gundersen, Lise-Lotte (2013). Strategies to 9-Substituted-8-oxoadenines. 28. Organisk-kjemisk vintermøte.
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2012, 25. desember). Her starter jakten på en ny medisin. [Internett].  Teknisk ukeblad.
• Gundersen, Lise-Lotte & Torheim, Norunn K. (2012, 14. desember). Møysommelig medisinjakt. [Internett].  www.forskningsradet.no.
• Hennum, Martin & Gundersen, Lise-Lotte (2012). Methodology towards the total synthesis of asmarines.
• Hennum, Martin; Odden, Hege Hortemo; Gundersen, Lise-Lotte & Hansen, Tore (2012). Methodology towards the total synthesis of asmarines.
• Kania, Jindrich & Gundersen, Lise-Lotte (2012). Methods for isomerisation of the double bond in N-allyl purines. Organisk-kjemisk vintermøte.
• Kania, Jindrich & Gundersen, Lise-Lotte (2012). Synthetic studies directed towards Asmarines.
• 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.
• Munack, Steffi; Leroux, Vincent; Roderer, Katrin; Ökvist, Mats; Bryntesen, Tina; Thiemicke, Alexander; Van Eerde, Jan Hendrik; Kast, Peter; Gundersen, Lise-Lotte & Krengel, Ute (2011). A structure-guided approach to new tuberculosis drugs – potential inhibiyors of Mycobacterium tuberculosis chorismate mutase.
• Gundersen, Lise-Lotte (2011). Organisk kjemi i utvikling av nye medisiner.
• Gundersen, Lise-Lotte (2011). Synthesis directed towards Agelasines and Asmarines: Marine Antibiotics.
• Gundersen, Lise-Lotte (2011). Synthesis directed towards bioactive compounds.
• 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.
• Gundersen, Lise-Lotte; Kania, Jindrich; Odden, Hege Hortemo; Proszenyak, Agnes & Vik, Anders (2011). Synthesis directed towards Agelasines and Asmarines; Marine Antibiotics.
• Gundersen, Lise-Lotte & Siah, Huey-San Melanie (2011). Synthesis of 9-substituted-8-oxoadenines as potential inhibitors of DNA repair enzymes in cancer therapy.
• Kania, Jindrich & Gundersen, Lise-Lotte (2011). Double bond migration in N-allyl purines, scope and limitation.
• Khoje, Abhijit Datta; Gundersen, Lise-Lotte & Charnock, Colin (2011). Deaza analogs of antimycobacterial 6-aryl-9-benzyl purines: Synthesis and biological activities.
• 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.
• 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.
• Lim, Fiona S. P.; Siah, Huey San Melanie & Gundersen, Lise-Lotte (2011). Synthesis of 8-bromo-9-substituted purines.
• 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.
• Odden, Hege Hortemo & Gundersen, Lise-Lotte (2011). Synthesis of alfa-functionalized allylamines employing the Overman rearrangement.
• Odden, Hege Hortemo & Gundersen, Lise-Lotte (2011). Synthesis of allylic amines as building blocks for asmarine analogs.
• Read, Matthew Lovell; Krapp, Andreas & Gundersen, Lise-Lotte (2011). Intramolecular Diels-Alder reaction on furan (IMDAF), resulting in new complex multicyclic fused ring systems.
• Siah, Huey San Melanie; Gundersen, Lise-Lotte & Gorbitz, Carl Henrik (2011). NMR and X-ray structural studies of 3-benzyl-8-bromoadenine.
• Gundersen, Lise-Lotte (2010). Nobelprisen i kjemi 2009 - Ada E. Yonath, Thomas A. Steitz og Venkatraman Ramakrishnan - studies of the structure and function of the ribosome.
• Kania, Jindrich & Gundersen, Lise-Lotte (2010). Synthetic studies directed towards asmarines.
• Kania, Jindrich & Gundersen, Lise-Lotte (2010). Synthetic studies directed towards asmarines.
• Khoje, Abhijit Datta; Kulendern, Aisvareya; Gundersen, Lise-Lotte; Charnock, Colin; Wan, Baojie & Franzblau, Scott (2010). Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycotbacterial activities.
• Khoje, Abhijit Datta; Kulendrn, Aisvareya; Charnock, Colin & Gundersen, Lise-Lotte (2010). Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycotbacterial activities. Compounds modified in the imidazole and/or pyrimidine ring.
• Kildahl-Andersen, Geir; Brændvang, Morten; Utenova, Bibigul t. & Gundersen, Lise-Lotte (2010). 6-Arylpurines as selective ligands for the various adenosine receptors.

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