519-23-3 Usage
Description
Ellipticine is an alkaloid isolated from Apocyanaceae plants that exhibits antitumor activities by intercalating into DNA and/or inhibiting DNA topoisomerase II. It forms covalent adducts in DNA after being enzymatically activated with cytochrome P450 isoforms (e.g., CYP3A4, CYP1A1, or CYP1A2) or by peroxidases in target tissues. Ellipticine has been shown to inhibit the proliferation of human breast adenocarcinoma MCF-7 cells, leukemia HL-60 and CCRF-CEM cells, neuroblastoma IMR-32, UKF-NB-3, and UKF-NB-4 cells, and U87MG glioblastoma cells with IC50 values ranging from 0.27-4.7 μM.
Definition
ChEBI: A organic heterotetracyclic compound that is pyrido[4,3-b]carbazole carrying two methyl substituents at positions 5 and 11.
Synthesis Reference(s)
Journal of the American Chemical Society, 102, p. 1457, 1980 DOI: 10.1021/ja00524a059The Journal of Organic Chemistry, 72, p. 7106, 2007 DOI: 10.1021/jo070774zTetrahedron Letters, 18, p. 4663, 1977 DOI: 10.1016/S0040-4039(01)83595-4
General Description
A topoisomerase II inhibitor. Acts as an intercalative alkaloid that stimulates topoisomerase II-mediated DNA breakage. Is also capable of uncoupling mitochondrial oxidative phosphorylation.
Biochem/physiol Actions
Cell permeable: yes
in vitro
treatment mammalian dna topoisomerase ii reaction mixture with ellipticine resulted in the stimulation of dna cleavage. the drug-stimulation of dna cleavage is related to the formation of a ternary complex between topoisomerase ii, dna, and ellipticine. ellipticine dose not inhibit enzyme-mediated dna religation, however, it stimulates dna breakage by enhancing the forward rate of cleavage [2]. ellipticine showed growth inhibition activity on l1210 lymphocytic leukemia cells with a ic50 of 0.99 μm [1].
in vivo
ellipticine was evaluated in p. berghei infected mice in the 4-day suppressive test. ellipticine had a 100% inhibition versus controls on days 5 and 7 at an oral dose of 50 mg/kg/day, and the mean survival time (mst) was more than 40 days [3].
IC 50
= 0.99 μm for l1210 lymphocytic leukemia cells [1]
Purification Methods
This DNA intercalator is purified by recrystallisation from CHCl3 or MeOH and is dried in vacuo. The UV max values in aqueous EtOH/HCl are at 241, 249, 307, 335 and 426nm. [Marini-Bettolo & Schmutz Helv Chim Acta 42 2146 1959.] The methiodide has m 360o(dec), with UV (EtOH/KOH) at 223, 242, 251, 311, 362 and 432nm. [Goodwin et al. J Am max Chem Soc 81 1903 1959, Beilstein 23/9 V 417.]
references
[1] paoletti c, cros s, xuong nd, lecointe p, moisand a. comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse l 1210 leukemia. chem biol interact. 1979 apr;25(1):45-58.[2] tewey km, chen gl, nelson em, liu lf. intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian dna topoisomerase ii. j biol chem. 1984 jul 25;259(14):9182-7.[3] rocha e silva lf, montoia a, amorim rc, melo mr, henrique mc, nunomura sm, costa mr, andrade neto vf, costa ds, dantas g, lavrado j, moreira r, paulo a, pinto ac, tadei wp, zacardi rs, eberlin mn, pohlit am. comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog. phytomedicine. 2012 dec 15;20(1):71-6.
Check Digit Verification of cas no
The CAS Registry Mumber 519-23-3 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 5,1 and 9 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 519-23:
(5*5)+(4*1)+(3*9)+(2*2)+(1*3)=63
63 % 10 = 3
So 519-23-3 is a valid CAS Registry Number.
InChI:InChI=1/C17H14N2/c1-10-14-9-18-8-7-12(14)11(2)17-16(10)13-5-3-4-6-15(13)19-17/h3-9,19H,1-2H3
519-23-3Relevant articles and documents
Oxazoles in organic chemistry. Synthesis of the antitumor agent ellipticine
Kozikowski,Hasan
, p. 2039 - 2040 (1977)
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Cosson,J.P.,Schmid,M.
, p. 1353 - 1354 (1970)
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Exploiting an intramolecular Diels-Alder cyclization/dehydro-aromatization sequence for the total syntheses of ellipticines and calothrixin B
Deng, Chengdan,Liu, Yuancui,Xu, Mei,Xie, Kaiqiang,Liu, Sheng
, p. 1395 - 1403 (2021)
The tetracyclic and pentacyclic skeletons of pyrido and quinolinocarbazole alkaloids have been synthesizedviaa unified strategy. The prominent key step involved a Diels-Alder intramolecular cyclization/dehydro-aromatization sequence. From these carbazole-lactam cores, linear syntheses have been developed for ellipticines and calothrixin B.
Regioselection Switch in Nucleophilic Addition to Isoquinolinequinones: Mechanism and Origin of the Regioselectivity in the Total Synthesis of Ellipticine
Castro, Joaquim A. M.,Ligiéro, Carolina B. P.,Maior, Christian R. S.,Miranda, Paulo C. M. L.,Morgon, Nelson H.,Naciuk, Fabrício F.,Rocco, Silvana A.,Serikava, Bruno K.
, (2022/03/02)
Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformation through density functional theory calculations reveals unexpected N-oxide assistance in cascade tautomerizations, which was crucial for directing the nucleophilic attack and hastening the overall process. Using this strategy, we prepared the aniline-isoquinolinedione adduct and submitted it to an intramolecular double C-H cross-coupling activation to furnish ellipticinequinone, which gave ellipticine after a MeLi addition/BH3reduction sequence.
Total Synthesis of Olivacine and Ellipticine via a Lactone Ring-Opening and Aromatization Cascade
Dilek, ?mer,Patir, Süleyman,Tilki, Tahir,Ertürk, Erkan
, p. 7901 - 7916 (2019/06/17)
Effective preparation of olivacine and ellipticine via late-stage D-ring cyclization is described. Key features of the synthetic routes include trifluoroacetic acid-mediated formation of a lactone that is fused to a tetrahydrocarbazole derivative and its one-pot two-step ring opening and aromatization mediated by para-toluenesulfonic acid and palladium on carbon, respectively.
