Z-Stereoselective Catalytic Synthesis of Natural Acids, Lembehynes, - PowerPoint PPT Presentation

Z-Stereoselective Catalytic Synthesis of Natural Acids, Lembehynes, and Acetogenins - Modern Preparations for Medicine Vladimir A. D'yakonov 1, *, Lilya U. Dzhemileva 1 , Alexey A. Makarov 1 , Regina A. Tuktarova 1 , Svetlana R. Ishmukhametova 1 , Evgenii N. Andreev 1 , and Usein M. Dzhemilev 1 1 Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation * Corresponding author: DyakonovVA@gmail.com 1

Z-Stereoselective Catalytic Synthesis of Natural Acids, Lembehynes, and Acetogenins - Modern Preparations for Medicine Graphical Abstract 2

Abstract: The report discusses the latest achievements of the authors in developing original methods for stereoselective synthesis of natural acetogenins, higher bis-methylene- separated di- and trienoic acids, lembehynes that are of exceptional interest as low- toxic target antitumor drugs, as well as compounds with neritogenic activity for treating neurodegenerative diseases. The synthetic approaches to the above listed natural compounds are based on the use at the key stage of the synthesis, of new organometallic reactions, such as Ti-catalyzed homo- and cross-cyclomagnesiation of 1,2-dienes, involving available Grignard reagents. The studies of the synthesized compounds for their antitumor and antibacterial activities in vitro were performed with the use of unique equipment in “Centre for Molecular Design and Biological Screening of Candidate Substances for the Pharmaceutical Industry” at the Institute of Petrochemistry and Catalysis of RAS using modern methods such as flow cytofluorometry, fluorescence microscopy and Western blotting. For compounds that showed the greatest activity, in vivo tests were performed for linear mice with grafted malignant Lewis carcinoma. Key words: Natural acetogenins; Higher bis-methylene-separated(interrupted) di- and trienoic acids; Lembehynes; Antitumor drugs; Neritogenic activity. 3

1,2 1,2-DIENES IN STEREOSELECTIVE DIENES IN STEREOSELECTIVE SYNTHESIS OF ALKENES SYNTHESIS OF ALKENES Hydrometalation Hydrometalation of of 1,2 1,2- -dienes dienes H-M (Al, Mg), [Cat] R R . + + R R S. Nagahara et el S. Nagahara et el. . Bull. Chem. Soc. Jpn. Bull. Chem. Soc. Jpn., 1993, 66, 3783. 1993, 66, 3783. Cycloalumination of Cycloalumination of 1,2 1,2- -dienes dienes Et 3 Al, [Zr] R . H + R Pr R CH 2 Cl 2 , ~90% Al Z = 100% Et U.M. Dzhemilev et al. Russ. Chem. Bull. U.M. Dzhemilev et al. Russ. Chem. Bull. 20 2002 02, , 51 51, , 2255 2255. Cyclomagnesiation of Cyclomagnesiation of 1,2 1,2- -dienes dienes EtMgHal, [Ti] R R . H + R R R THF , 85-92% Mg Z,Z = ~98% U.M. Dzhemilev et al. U.M. Dzhemilev et al. Tetrahedron Tetrahedron., ., 20 2004 04, , 60 60, , 1287 1287.

INTERMOLECULAR CYCLOMAGNESIATION OF ALKYL(ARYL) INTERMOLECULAR CYCLOMAGNESIATION OF ALKYL(ARYL) ALLENES AND N,O ALLENES AND N,O-CONTAINING CONTAINING 1,2 1,2-DIENES DIENES . C 6 H 13 C 6 H 13 () n R 2 N C 6 H 13 R 2 N ( ) n Mg 70-85 70 85% [Ti], Mg H + R EtMgBr . N ( ) n R n = 1, 2 . R 2 N Вn Вn () n Bn R 2 N ( ) n Mg 80 80-85 85% [Ti] = Cp 2 TiCl 2 ; R = Et, i-Pr, -(CH 2 ) 5 -, -C 2 H 4 -O-C 2 H 4 -. N-containing 1,2 containing 1,2-diene:cyclo diene:cyclo-1,2 1,2-diene:EtMgBr:Mg:[Ti]= 10:12:26:20:1; Et diene:EtMgBr:Mg:[Ti]= 10:12:26:20:1; Et 2 O, 6 h, r. t. O, 6 h, r. t. . C 6 H 13 C 6 H 13 () n THPO C 6 H 13 THPO ( ) n Mg 80-95 80 95% [Ti], Mg H + EtMgBr . THPO ( ) n n = 1, 2 . Вn THPO () n Вn Bn THPO ( ) n Mg 85 85-90 90% O-containing 1,2 containing 1,2-diene:cyclo diene:cyclo-1,2 1,2-diene:EtMgBr:Mg:[Ti]= 10:11:24:20:0.5; Et diene:EtMgBr:Mg:[Ti]= 10:11:24:20:0.5; Et 2 O, 6 h, r. t. O, 6 h, r. t. V.A. D’yakonov, A.A. Makarov, E.Kh. Makarova, U.M. Dzhemilev, Tetrahedron. – 2013, V. 69, P. 8516-8526 5

NATURAL SOURCES OF 5 Z ,9 NATURAL SOURCES OF 5 ,9 Z -DIENOIC ACIDS DIENOIC ACIDS Aplysina fistularis Aplysina fistularis Natural Natural 5 Z ,9 ,9 Z -dienoic dienoic acids acids COOH R Erylus formosus Erylus formosus R  (CH 2 ) n CH 3 R (n = 15  30) Pinus Pinus koraiensis koraiensis Chondrilla nucula Chondrilla nucula Pinus Pinus tabulaeformis tabulaeformis Isolated Isolated from from the the marine marine sponges sponges (Aplysina Aplysina fistularis fistularis, , Axinella Axinella verrucosa verrucosa) ) and and seeds seeds tabulaeformis ) (Pinus Pinus tabulaeformis Carballeira Carballeira N.M., et al. N.M., et al. J. Nat. Prod., 2002, 64, J. Nat. Prod., 2002, 64, Dictyostelium Dictyostelium 1715 1715 Axinella Axinella verrucosa verrucosa discoideum discoideum Microciona Microciona prolifer prolifer Efficient inhibitors of Efficient inhibitors of topoisomerases topoisomerases I and I and II II; ; simultaneously exhibit antitumor, simultaneously exhibit antitumor, antiviral antiviral, , antiparasitic and antiparasitic and antibacterial antibacterial activities activities 6

KNOWN KNOWN METHODS FOR THE SYNTHESIS OF METHODS FOR THE SYNTHESIS OF 5 Z ,9 ,9 Z -DIENOIC ACIDS DIENOIC ACIDS O (a) (b) O + O O H Br H O (d) (c) O O 4 стадии, выход 12% 4 стадии, выход 12% CO 2 H 2 изомера 2 изомера + (a) n-BuLi, -70 o C; (b) H 2 , Lindlar; (c) HCl, 60 o C; CO 2 H (d) Ph 3 P + (CH 2 ) 4 CO 2 HBr - , 2.5 M n-BuLi. Prof. Nestor Prof. Nestor Carballeira Carballeira N.M. Carballeira, A. Emiliano, A. Guzman. Chem. Phys. Lipids, 100, (1999), 33-40 University of Puerto Rico University of Puerto Rico N.M. . Carballeira Carballeira, , J.E. . Betancourt Betancourt, , E.A A. . Orellano Orellano, , F.A. .A. Gonzalez Gonzalez. . J. Nat. J. Nat. Prod Prod, 65, (2002), 1715 , 65, (2002), 1715-1718 1718 13 13 стадий, выход стадий, выход 12 12% Prof. Christian B. W. Stark Prof. Christian B. W. Stark J. Adrian J. Adrian , C. B. W. Stark, Eur. J. Org. C. B. W. Stark, Eur. J. Org. Chem Chem, , 27 27, (20 , (2016 16), 4607 ), 4607-4610 4610 Universität Hamburg Universität Hamburg 7

EFFICIENT SYNTHESIS OF EFFICIENT SYNTHESIS OF 5 5 Z ,9 ,9 Z -DIENOIC ACIDS DIENOIC ACIDS The cyclomagnesiation reaction of allenes to give 2,5 The cyclomagnesiation reaction of allenes to give 2,5-dialkylidenemagnesacyclopentanes dialkylidenemagnesacyclopentanes Known Known EtMgHal H 3 O+ R R R . Natural Natural R [Ti] R Mg 5 Z ,9 ,9 Z -dienoic dienoic acids acids Dzhemilev U.M., et al. Tetrahedron, 2004, 60, 1287 Dzhemilev U.M., et al. Tetrahedron, 2004, 60, 1287 D’yakonov V.A., et al. Tetrahedron, 2008, 64, 10188 D’yakonov V.A., et al. Tetrahedron, 2008, 64, 10188 R COOH NEW METHOD NEW METHOD : Stereoselective Stereoselective synthesis of practically important synthesis of practically important 5 Z ,9 ,9 Z -dienoic acids dienoic acids  (CH 2 ) n CH 3 R = is based on the new reaction. is based on the new reaction. (n = 15  30) . Isolated from the marine Isolated from the marine EtMgHal H 3 O+ R (CH 2 ) 4 -OR' R sponges (Aplysina sponges (Aplysina + Mg . [Ti] 82-85% fistularis, Axinella fistularis, Axinella R'O-(CH 2 ) 4 verrucosa) and seeds verrucosa) and seeds (Pinus tabulaeformis ) (Pinus tabulaeformis [O] R R (CH 2 ) 3 -COOH (CH 2 ) 4 -OR' 71-74% Carballeira N.M., et al. Carballeira N.M., et al. J. Nat. Prod., 2002, 64, J. Nat. Prod., 2002, 64, 1715 1715 Russ.Chem.Bull Russ.Chem.Bull., 2012, ., 2012, 61(1),15 61(1),158; 8; Russ.J Russ.J. . Org.Chem Org.Chem., 2012, 48 , 2012, 48(3) (3), 3 , 349 49; ; Tetrahedron, 2013, 69, 8516; Tetrahedron, 2013, 69, 8516 ; Chem.Commun Chem.Commun., 2013, 49, 8401 ., 2013, 49, 8401. 8

IN VITRO STUDY ON TOPOISOMERASE I INHIBITORY ACTIVITY OF THE IN VITRO STUDY ON TOPOISOMERASE I INHIBITORY ACTIVITY OF THE SYNTHESIZED SYNTHESIZED 5 Z ,9 ,9 Z -DIENOIC ACIDS DIENOIC ACIDS R (CH 2 ) 3 -COOH Fig Fig. Electrophoregram Electrophoregram of of the the products products of of relaxation relaxation of of supercoiled supercoiled plasmid plasmid DNA DNA in in vitro vitro induced induced by by topoisomerase topoisomerase I ( (Topogen Topogen, USA) USA) in in the the presence presence of of (5Z, Z,9Z) Z)-5,9-eicosadienoic eicosadienoic acid. 1. Supercoiled acid Supercoiled plasmid plasmid DNA DNA (pHOT (pHOT1). 2. Relaxed Relaxed DNA DNA form form ( (visualization visualization of of the the set set of of topoisomers topoisomers). 3. Negative Negative control control with with DMSO DMSO (concentration concentration 3%). 4. Relaxation Relaxation reaction reaction of plasmid of plasmid DNA DNA in in the the presence presence of of camptothecin camptothecin (10 10 μM) M). 5–9. V. A. V. A. D’yakonov D’yakonov, A. A. , A. A. Makarov Makarov, L. U. , L. U. Dzhemileva Dzhemileva, Effect of Effect of different different concentrations concentrations of of (5Z, Z,9Z) Z)-5,9-eicosadienoic eicosadienoic E. H. Makarova E. H. Makarova, U. M. , U. M. Dzhemilev Dzhemilev, , Chem. Chem. Commun Commun ., ., acid acid on on the the relaxation relaxation of of plasmid plasmid DNA DNA (5 – 0.75 75, 6 – 0.5, 7 – 2013, 49, 8401 2013, 49, 8401 0.25 25, 8 – – 0.1, 9 – 0.01 01 μM) M). 9