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Home , Acridine, Acridine orange, Dibenzazepine, Proflavine

"...the step from the laboratory to the patient's bedside...is extraordinarily arduous and fraught with danger." Paul Ehrlich Baran Group Meeting Jonathan Lockner

Dyes to Drugs: 1 9 8 acridine 2 7 dibenzo(b,e) Orange 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 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 N 9.09 8.19 135.8 129.5 Cl N 1H NMR: 13C NMR: 7.64 128.3 quinacrine/Mepacrine/Atebrin /Amsidyl (antileukemia) H2N N NH2 (antimalarial) 125.5 N 7.89 N 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 (Carl Grabe & Heinrich Caro, BASF, Germany) Grabe introduced "ortho", "meta", "para" nomenclature 1895 → "Orange Dye" patent; acridines being used as fabric & biological 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 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 (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 & 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) selective fluorescent dye N Br Useful for cell cycle determination: stain nucleic acids; N Hydrophobic → quickly diffuses into cell membrane, then complexes with DNA (green N O ) 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 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 (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- 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 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 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 () 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. Czech. Chem. Commun. 1977, 42, 2802 N H H H NH CONH chlomacran 2 2 () Br Zirkle U.S. Patent 1964, 3131190 2 N NaOH N tacrine/Cognex (antidementia) acetone Cl NMe2 O N H2SO4 N N N O H H NH O NMe CN CuCl 2 HO Holm Br. Patent 1963, 933875 (antidepressant) N NH2 H N

Shutske, G. M.; et al J. Med. Chem. 1988, 31, 1278

Lednicer, D. Strategies for Organic Drug Synthesis and Design, NH OH NH O John Wiley & Sons, New York, 1998, pp. 383-387 2 2 LiAlH4 hydroxyl improves oral absorption N N velnacrine (antidementia) 1 9 8 2 7

3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner

1. K2CO3, Cu, CuBr O CO2H NMP, 160 °C, 98% + Cl N N NH 2. H2SO4, 86% 2 N N N Me CO2H H H Me COR N HN HN N OMe H

SOCl2, DMF Cl N N MeO NHSO2Me quinpramine (antiprion) HN intron splicing agent (for Creutzfeldt!Jakob disease) Cl Bioorg. Med. Chem. HCl, CHCl3!NMP 1997, 5, 1185

N 99% N Ph N Me CONHMe Me COR H N asulacrine/amsalog/CI-921 N (anticancer) R=Cl OMe MeNH2 J. Het. Chem. 1989, 26, 1469 N R=NHMe H2O!CHCl3 N N OMe HO NH (!)-TAN-67 tacrine-PIQ hybrid (antinociceptive) (fM AChE inhibitor) " opioid receptor agonist Sharpless "click" N J. Am. Chem. Soc. (+) isomer induced hyperalgesia 2005, 127, 6686 (opposite effect!) Cl Cl HO C N,N-dimethylaniline MeO 2 MeO HO2C NMe2 !, 18 h + N NH Cl 83% H HN 2 NO NO2 2 O O POCl3, N,N-dimethylaniline N N N N N NMe 1,2-DCE, reflux, 1 h H H 2 88% N N BRACO-19 H2NHN NMe2 O Cl telomerase inhibitor MeO MeO Neidle et al. J. Med. Chem. 2003, 46, 4463 N THF!MeOH H rt, 7.5 h N NO2 89% H NO2 PZA/pyrazoloacridine (antitumor) J. Med. Chem. 1992, 35, 4770 1 9 8 2 7

3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner

Natural Product Synthesis: Amphimedine Amphimedine Stille, J. Am. Chem. Soc. 1988, 110, 4051 Nakahara, Heterocycles 1988, 27, 2095

MeO cat. pyridine MeO OSO CF MeO NO MeO O pTs O 2 3 MeO NHR PhMe 2 2 Pd(PPh3)4 NO 2,6-lutidine A, LiCl + 2 140 °C O NH2 O DMAP 1,4-dioxane "quant" N N N MeO N O H CH Cl 100 C H MeO 2 2 MeO ° MeO EtO O MeO 92% 87% R=t-BuOCO 1. TFA 2. TFAA 80% H2SO4, 75 °C 53% R=CF3CO DIPEA, THF 94% CAN NHBoc CH3CN!H2O, rt PCl SnMe3 85% CAN MeO NO2 5 MeO NO2 O NO2 POCl CH CN!H O 3 (A) O NHCOCF3 3 2 O NHCOCF3 O 66% 1. B, THF, rt 0 C ° N Cl N O N Cl 77% H HN MeO MeO N 2. pyr•HF O 48% N O 1. B, CHCl , 35 C; H+ O 3 ° 1. B, dry acid-free 2. MeI, K CO , DMF, 7% TBDMSO 1. 6M HCl, THF 2 3 2. Me2SO4, K2CO3 CHCl3, rt N DMF, 84% 2. MeOH, 64%

O NO2 N OTBDMS H2, Pd/C O Et N O Ghosez's diene (B) 3 N O NHCOCF3 N N O N Cl MeOH, rt N 13% N O O N N amphimedine O O (0.25% overall) amphimedine O N OTBDMS (26% overall) H unprecendented [4+2] O N O [4+2] N Michael N N

MeO S N S S O O O kuanoniamine A Nakahara, Tetrahedron 1997, 53, 17029 Hepburn, Heterocycles 2006, 68, 975 1 9 8 2 7 For other pyridoacridines, see Chem. Rev. 1993, 93, 1825 3 N 6 Baran Group Meeting 4 10 5 Acridine Alkaloids Jonathan Lockner

Natural Product Synthesis: Ascididemin (X=H) and 2-Bromoleptoclinidinone (X=Br) Bracher, F. Heterocycles 1989, 29, 2093 N3 H HONH3Cl N3 Bracher, F. Liebigs Ann. Chem. 1990, 205 AcO CH3CN AcO

O O reflux CeCl •7H O from O OEt N N 3 2 O N 56% EtOH bottom left O + X NH 20 °C, 16 h X N 2 H N3 N O 62-78% O 3 H SO AcOH (1:10) 2 4! O3, MeOH, !78 °C; reflux, 10 min then Me2S, 77% 90-94% N O 1. HC(OEt) NMe N 2 2 N 1. isopropenyl acetate, cat TfOH DMF, 120 °C, 1 h N N 3 2. DDQ, PhMe, reflux, 15 min 3 X N X N AcO AcO 2. NH4Cl, AcOH, reflux O 1 h, 59-69% O 3. NaHCO3, H2O!MeOH, rt, 12 h ascididemin (X=H) N 40% N 2-bromoleptoclinidinone (X=Br) OH O "ketone" (KO3S)2NO, MeOH phosphate buffer, rt, 56% Ascididemin Moody, C. J.; Rees, C. W.; Thomas, R. Tetrahedron Lett. 1990, 31, 4375 I I N O N3 N N 2-iodoaniline PhMe N Et Al H SO AcO AcO AcO 3 HO HN BaMnO4 O N 2 4 ascididemin reflux !N2 (see above) 80% CH2Cl2 CH Cl h" O N O N HO N N N 2 2 79% 83% 32% O O O N N N N Ac2O, pyridine, 99% or Tf2O, DIPEA, CH2Cl2, 90% N H The Cystodytins R N Ciufolini, M. A.; Byrne, N. E. J. Am. Chem. Soc. 1991, 113, 8016 O N N HO AcO AcO O CH2=CHOEt N3 1. 10% NaOH, EtOH, 0 °C 1,2-DCE cystodytin A (R= RO N + R=OAc O OHC 2. Ac2O, pyridine, 88% Yb(fod)3 R=OTf reflux cystodytin B (R= triflate proved entirely resistant to Ortar deoxygenation; N3 O N3 99% O successful completion of NPTS required rerouting from "ketone" cystodytin C (R= OH (more PG operations; amide moieties introduced much earlier)