6295-21-2Relevant articles and documents
OXOBENZINDOLIZINOQUINOLINES AND USES THEREOF
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Page/Page column 30, (2009/12/23)
The synthesis of aromathecins, substituted 12H-5,l la-diazadibenzo[b,h]fluoren- 11 -ones is described. Use of these cytotoxic compounds and pharmaceutical compositions containing them for the treatment of cancer is described. Two novel processes for the synthesis of this system and a series of 14-substituted aromathecins as novel cytotoxic, topoisomerase I poisons are described.
Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors
Cinelli, Maris A.,Morrell, Andrew,Dexheimer, Thomas S.,Scher, Evan S.,Pommier, Yves,Cushman, Mark
experimental part, p. 4609 - 4619 (2009/07/04)
The aromathecin or "rosettacin" class of topoisomerase I (top1) inhibitors is effectively a "composite" of the natural products camptothecin and luotonin A and the synthetic indenoisoquinolines. The aromathecins have aroused considerable interest following the isolation and total synthesis of 22-hydroxyacuminatine, a rare cytotoxic natural product containing the 12H-5,11a-diazadibenzo[b,h]fluoren-11-one system. We have developed two novel syntheses of this system and prepared a series of 14-substituted aromathecins as novel antiproliferative topoisomerase I poisons. These inhibitors are proposed to act via an intercalation and "poisoning" mechanism identical to camptothecin and the indenoisoquinolines. Many of these compounds possess greater antiproliferative activity and anti-top 1 activity than the parent unsubstituted compound (rosettacin) and previously synthesized aromathecins, as well as greater top1 inhibitory activity than 22-hydroxyacuminatine. In addition to potentially aiding solubility and localization to the DNA-enzyme complex, nitrogenous substituents located at the 14-position of the aromathecin system have been proposed to project into the major groove of the top1-DNA complex and hydrogen-bond to major-groove amino acids, thereby stabilizing the ternary complex.
Pseudoacids. II. 2-Acylbenzoic Acid Derivatives
Valente, Edward J.,Martin, Samuel B.,Sullivan, Larry D.
, p. 264 - 276 (2007/10/03)
Structures of derivatives of cyclic o-acylbenzoic acids, including the chloride, endo- and exocyclic amides, esters and anhydrides, are examined. 3-Chloro-1(3H)-isobenzofuranone (1), orthorhombic, Pbca, a = 11.616 (5), b = 8.120 (3), c = 15.640 (9) A; 3-methoxy-3-phenyl-1(3H)-isobenzofuranone (3), orthorhombic, P212121, a = 6.923 (2), b = 8.291 (4), c = 21.551 (8) A; 3-hydroxy-3-phenyl-N-propyl-1(3H)-isoindolone (4), orthorhombic, P212121, a = 8.662 (4), b = 9.551 (7), c = 17.649 (14) A; 3-(N-morpholino)-1(3H)-isobenzofuranone (5), triclinic, P1, a = 6.172 (4), b = 11.163 (7), c = 17.33 (2) A, α = 105.91 (6), β = 99.85 (6), γ = 97.57 (5)°; 3-(2′-benzoylbenzoyloxy)-3-phenyl-1(3H)-isobenzofuranone (7), triclinic, P1, a = 9.694 (3), b = 10.505 (4), c = 11.163 (4) A°, α = 80.58 (3), β = 80.41 (3), γ = 76.49 (3)°; bis[1(3H)-isobenzofuranone-3-yl]ether (8), monoclinic, I2/a, a = 15.31 (2), b = 6.111 (12), c = 28.30 (5) A, β = 101.61 (12)°. An open oxoacid tertiary amide is also described: N-morpholino 2′-benzoylbenzamide (6): monoclinic, P21/c, a = 6.844 (4), b = 15.696 (8), c = 14.154 (7) A, β = 99.43 (4)°. Pseudoacid derivatives form planar isobenzofuran and isoindole rings, and the former aldehyde/ketone carbon-heteroatom endocyclic and exocyclic bond distances show bond length variations which correlate with the relative basicities of the attached groups. Structures of both endocyclic and exocyclic nitrogen pseudoamides are reported as well as examples of the normal-pseudoanhydride and the dipseudoanhydride.