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Acridine Alkaloids Jonathan Lockner

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Acridine Alkaloids Jonathan Lockner "...the step from the laboratory to the patient's bedside...is extraordinarily arduous and fraught with danger." Paul Ehrlich Baran Group Meeting Acridine Alkaloids Jonathan Lockner Dyes to Drugs: 1 9 8 acridine 2 7 dibenzo(b,e)pyridine Orange Dye 2,3,5,6-dibenzopyridine U.S. Patent 537723 A, April 16, 1895 (Swiss chemists) 3 N 6 2,3-benzoquinoline 4 10 5 10-azaanthracene Cancer Treatment Using Specific 3,6,9-Substituted Acridines WO2006095139, September 14, 2006 (Neidle et al) 3,6,9 are the important positions of acridine drugs flat (planar) aromatic, hydrophobic, pKa 5.6 colorless to light yellow crystals (mp 107-110 °C) chromatography on basic alumina MeO NHSO2Me irritating odor, lachrymator, carcinogenic, mutagenic H2N N NH2 → Bruce N. Ames (UC Berkeley) studied carcinogenesis/mutagenesis by NEt2 HN chemicals, including acridines (Science 1972, 176, 47) Cl- Me HN OMe 126.6 acriflavine N 9.09 8.19 135.8 129.5 Cl N 1H NMR: 13C NMR: 7.64 128.3 quinacrine/Mepacrine/Atebrin amsacrine/Amsidyl (antileukemia) H2N N NH2 (antimalarial) 125.5 N 7.89 N proflavine 130.3 8.22 "There is no exaggeration that [the 149.1 availabiilty of quinacrine] probably changed the course of history." L. J. Bruce-Chwatt 1870 → acridine isolated from coal tar (Carl Grabe & Heinrich Caro, BASF, Germany) Grabe introduced "ortho", "meta", "para" nomenclature 1895 → "Orange Dye" patent; acridines being used as fabric dyes & biological staining agents 1912 → Ehrlich & Benda proposed use of acridines as antimicrobials (acriflavine/Trypaflavin/Gonoflavin) Ehrlich (of Salvarsan "606" fame) first introduced idea of synthetic chemotherapy 1913 → Carl Browning identified proflavine, the neutral (non-methylated) version of acriflavine 1914-1918 → WWI; acridines as wound antiseptics in base hospitals on Western Front 1917-1946 → widespread clinical use of acridines as antibacterials during "antibacterial gap" 1939-1945 → WWII; quinacrine used in eastern theatres, in absence of quinine from Japanese-held Java 1946 → end of WWII, penicillins eclipse acridines 1970s → nitracrine/Ledarkin; amsacrine/Amsidyl for cancer treatment present → anticancer, anti-AChE, antiprion, antinociceptive 1 9 8 2 7 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner Commercial Availability of Acridines: Acridine Isolation: O marine: plant: NH2 CO2H a) tunicates & ascidians a) bark of Australian scrub ash tree b) sponges c) sea anemones N H N N N 9(10H)-acridanone acridine 9-aminoacridine 9-acridinecarboxylic acid $18.84/g $3.23/g $1.19/g $21/g mp >300 °C mp 107-110 °C O O N H N O N O N N N N H2N N NH2 O acridine orange (AO) acridine yellow (AY) cystodytin A acronycine $2.56/g $2.19/g + H2N N NH2 Cl- Me H N N NH 2 2 H2N N NH2 Acriflavine (Trypaflavin) chrysaniline ("phospin") benzoflavin $0.87/g dyes silk & wool yellow $25.91/g staining with AO: Acridine Biosynthesis: HO OH OH CO2H + NH2 OH N OH anthranilic acid phloroglucinol 2,4-dihydroxyacridine (or equiv) (or equiv) Chem. Rev. 1993, 93, 1825 Adv. Het. Nat. Prod. Syn. 1992, 2, 377 Die Pharmazie 1970, 25, 777 Australian J. Sci. Research 1951, 423 1 9 8 2 7 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner Using Acridine Dyes to Study Cellular Processes: absorption: 440-480 nm (blue) emission: 520-650 nm (green-red) N N N "metachromatic fluorochrome" NH2 acridine orange (AO) nucleic acid selective fluorescent dye N Br Useful for cell cycle determination: stain nucleic acids; flow cytometry N Hydrophobic → quickly diffuses into cell membrane, then complexes with DNA (green N O fluorescence) and RNA (red fluorescence) H AO/EDTA mixture used for 1) denaturing dsRNA, and 2) binding ssRNA 9-amino-6-bromo-DACA Darzynkiewicz, Z. Methods in Cell Biology 1990, 33, 285 Jaroszeski, M. J. Methods in Molecular Biology 1998, 91, 10 Cl J. Med. Chem. 1999, 42, 536 N acridinecarboxamide complexed with hexanucleotide d(CG(5-BrU)ACG)2 HN Cl (CG-preferential behavior associated with acridine chromophore) OMe Cl N quinacrine mustard MeO NHSO2Me fluorescence studies of plant, animal, human chromosomes Science 1970, 170, 762 O2N HN N HN N N Interaction of Acridines with DNA: nitracrine/Ledakrin amsacrine/Amsidyl (antitumor) (antileukemia) "Single action": 9-aminoacridine; quinacrine; acridine orange J. Med. Chem. 1992, 35, 4832 J. Med. Chem. 1974, 17, 922 1) intercalate DNA "Dual action": quinacrine mustard 1) intercalate DNA MeO NHSO2Me 2) form covalent bond with DNA NMe2 Intercalative activity (and thus mutagenicity) can be 'designed out' of the aminoacridine profile HN N N → Appropriately substituted acridines maintain anticancer potency by instead interfering with MeO topoisomerase II enzyme (e.g. amsacrine stabilizes DNA/topo II "cleavable complex") N N H Lerman, L. S. Proceedings of the National Academy of Sciences 1963, 49, 94 NO J. Antimicrobial Chemotherapy 2001, 47, 1 Me CONHMe 2 Current Med. Chem. 2002, 9, 1655 asulacrine/amsalog/CI-921 PZA/pyrazoloacridine (anticancer) (antitumor) J. Het. Chem. 1989, 26, 1469 J. Med. Chem. 1992, 35, 4770 Prager, R. H.; Williams, C. M. Science of Synthesis 2004, 15, 988 1 9 8 Demeunynck. M. Expert Opin. Ther. Patents 2004, 14, 55 2 7 Chiron, J.; Galy, J.-P. Synthesis 2004 313 Albert, A. The Acridines, 2nd ed.; Edward Arnold Ltd: London, 1966 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner Usual Acridine Synthesis Methodology: From quinomethanes: CO2H Ph Ph Ph Ph Cu ZnCl2 H2N O OH NH2 X ! CO2H Cyclization 160 °C HO N HO NH2 4 h HO NH HO N Cu N N CO2H H H ! 2-carboxy-diphenylamine Acridone From nitroarenes (Tanasescu 1937): X H2N OH X = Halogen Ullmann-Jourdan Reduction R CHO 1 H2SO4 R1 O R2 OH O R1 NO 20 °C N+ R1 Cyclization: POCl ; H SO ; PPA, etc..., 2 3 2 4 Oxidation O- Reduction: Na, BuOH, !, etc..., + N R2 N R2 Oxidation: CrO3; NaOH aq.; FeCl3; HNO3, etc... N N H O- OH Acridine Acridane From diphenylamines and carboxylic acids (Bernthsen 1884): RCO2H R Pfitzinger 1886: improved by µW " ZnCl OH OH 2 (J. A. Seijas, M. P. Vazquez-Tato) O HO2C OH N 200-270 °C 120 °C N 4 h H O + N HO OH Via radical reactions of quinones (Chuang 1990): H N OH O O CO2Et Friedländer: Mn(OAc)3 Cl Cl O MeCN 120 °C + NC CO2Et 58% N 80 °C, 36 h N + H 43% O O NH3Cl O N Via aza-Diels"Alder (del Mar Blanco 2000): Ullman 1906: NMe2 N O NaOAc Ph N O MeCN, 70 C O O N 150 °C O N ° 2 Ph 88% 2 + then NaOH + H N N Cl 2 N NH O 43% O O CF3 K CO alumina OMe 2 3 OMe From acylated diphenylamines: + Cu, CuI 20% Br N OMe H2N OMe Ph Goldberg: I , HI, h# Cl 2 N CO2H 63 % CO H POCl3 H N 2 K2CO3, Cu + O Ph reflux, 1 h N Cl H2N CyOH, reflux N H 1 9 8 2 7 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner Reductive Alkylation: nBu Electrocyclizations: Ring Expansion: h N Cl h" " AcO OAc OH OH N N nBuCO H ! N2 N N 2 N ! CO O Tetrahedron 1969, 25, 1125 H2SO4 ! HCl O 64% Photoalkylation: CH2OH ! CO2 N O O h" H Ring Contraction: NH OH N OH P H OH H N+ CH3OH N X- Via arylation of phenylacetonitriles (Makosza 1973): I2, AcOH Me Me Cl N Chem. Ber. 1964, 97, 2418 CN peracids H H2O N Et CN Et Et dibenzazepine 92% O N 90% aq H2SO4 Et 2 NH2 + CN 50 °C, 2 h + BF3•OEt2 PTC O2N N N Dehydrogenation: O- Pd/C PhH PCl N3 N 95% 3 5% 65 °C, 80 h N 270-300 °C N 69% Photolysis or pyrolysis of aryl azides: 6 h ARKIVOC 2006, (xii), 111 700 °C 350 °C Substitution at 9-position: 95% 90% N N N iPrCO H 3 H 2 AgNO3 From diarylamines (this example also shows that carbonyl can be generated after N-arylation): N H2SO4 N (NH ) S O NH 4 2 2 8 2 CHO I2 PbO2 + O N 240 °C N N MeO OMe NH2 N N Li H H MeO OMe N Via the McFadyen!Stevens Reaction: THF, !70 °C TMS 88% N O CO Me H 2 N CHO SOCl2 TsN O NaOH H2NNH2 Acridine 10-oxides: then O N 100 C, 2 h TsNNH N ° KO2, DMSO H 2 H 73% Cl N Cl rt, 18 h H Cl mCPBA 61% 59% N N N OH + AcOH, HCl N N+ CN - NH HN O 120 °C, 1 h N KCN 100% K [Fe(CN) ] Cl NiCl2•2H2O, Li, biphenyl 3 6 N+ Cl Cl 70 C, 3 h 64% ° - 35% O 1 9 8 2 7 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner Drug Synthesis: OH Cl CO2H 1. KCN NaBH4 OMe 2. NaOH O N Cl N Cl CO H CO2H N Cl 2 H2N OMe POCl3 H OMe Ac Ac Cl Cl Cl N PPA H Cl N Zirkle et al J. Org. Chem. 1961, 26, 135 H P2O5 Mietzsch et al U.S. Patent 1938, 2113357 OPOx 1. H2 N N NEt2 Cl 2. Me2N(CH2)3Cl HN Cl H NMe NaH Cl N Cl Bayer 1932 OMe NEt OMe 2 H H N 2 important WWII drug; 2 chlorimipramine cf. quinine (antidepressant) Cl N Cl N quinacrine/Mepacrine/Atebrin (antimalarial) H NOC O CONH 2 2 O O O NMe2 NMe2 O N O ClMg NMe H2 NaNH NH N 2 Cl Cl H 2 2 H Cl ! N N Bielavsky Collect.
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