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. 2008 Aug 14;51(15):4609-19.
doi: 10.1021/jm800259e. Epub 2008 Jul 17.

Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors

Maris A Cinelli  1 , Andrew Morrell, Thomas S Dexheimer, Evan S Scher, Yves Pommier, Mark Cushman
Affiliations

Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors

Maris A Cinelli et al. J Med Chem. .

Abstract

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 12 H-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-top1 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.

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Figures

Figure 1
Figure 1
Representative top1 inhibitors.
Figure 2
Figure 2
Structures of irinotecan and topotecan
Figure 3
Figure 3
Ligand overlay of aromathecin 27d (green) and indenoisoquinoline 4 (magenta). The positions of the lactam nitrogen and 14-position are indicated in their respective colors. The carboxylate group of 4 is perpendicular to the plane of the ring system.
Figure 4
Figure 4
Top1-mediated DNA cleavage induced by aromathecins 27a,d,g,i, 28d, and 28f: (lane 1) AG; (lane 2) DNA alone; (lane 3) top1 alone; (lane 4) camptothecin (1), 1 μM; (lane 5) 5, 1 μM; (lane 6) rosettacin (9), 100 μM; (lanes 7-30) (for compounds 27a,d,g,i, 28d, and 28f) Top1 + indicated compound at 0.1, 1, 10, and 100 μM, respectively.
Figure 5
Figure 5
Hypothetical model for the binding of aromathecin 27d in the ternary complex of DNA, top1, and the inhibitor. The diagram is programmed for wall-eyed (relaxed) viewing.
Scheme 1<sup>a</sup>
Scheme 1a. aReagents and Conditions
(a) EtOCOCl, CHCl3, reflux; (b) i. NaH, benzene, reflux, ii. methyl acrylate, reflux, iii. 6 M HCl, reflux; (c) ethylene glycol, cat. p-TsOH, benzene, reflux; (d) KOH, H2O, reflux; (e) cat. FeCl3, SOCl2, reflux; (f) THF, Et3N, r.t.; (g) polyphosphoric acid, 85% phosphoric acid, CH2Cl2, 100 °C.
Scheme 2<sup>a</sup>
Scheme 2a. aReagents and Conditions
(a) i. cat. 2-cyclohexen-1-one, cyclohexanol, reflux, ii. maleic acid, EtOAc, r.t.; (b) MeOH, Et3N, r.t.; (c) PDC, CH2Cl2, reflux; (d) polyphosphoric acid, CHCl3, reflux.
Scheme 3<sup>a</sup>
Scheme 3a. aReagents and Conditions
(a) i. BCl3·Me2S, 1,2,-dichloroethane, 0 °C, ii. chloroacetonitrile (for synthesis of 25), 4-chlorobutyronitrile (for synthesis of 26), AlCl3, reflux. iii. 2 M HCl, reflux; (b) p-TsOH, benzene, reflux.
Scheme 4<sup>a</sup>
Scheme 4a. aReagents and Conditions
(a) amine or amine salt + Et3N, DMSO, r.t., 62-100 °C (27d); (b) NaN3, DMSO; (c) i. (EtO3)P, benzene, reflux, ii. 3 M HCl, MeOH, reflux.
Scheme 5<sup>a</sup>
Scheme 5a. aReagents and Conditions
(a) amine, NaI, DMSO, 100 °C, then CF3COOH, CHCl3; (b) NaN3, DMSO, 100 °C (c) i. (EtO)3P, benzene, reflux, ii. 3 M HCl, MeOH, reflux.
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