Plasma stability of two glycosyl indolocarbazole antitumor agents.
In recent years, several glycosyl indolocarbazole derivatives have been developed as antitumor agents targeting the topoisomerase I-DNA complex and a few of them were evaluated in clinical trials. The lead drug in the series is compound A which bears a formylamino substituent on the N-imide F-ring. This compound has shown promising antitumor activities in vivo and was tested clinically but it has been recently replaced with a more active analogue, J-107088, bearing a (hydroxymethyl-2-hydroxy) ethylamino substituent on the N-imide F-ring. We have compared the plasma stability of two molecules in this series, compounds A and D, which only differ by the nature of the group on the imide ring. The conversion of the compounds into the anhydride species B was studied by HPLC and the resulting metabolite, formed both in human plasma ultrafiltrate and in water, was characterized by NMR and mass spectrometry. Absorption measurements provided a facile method to follow the conversion of compounds A and D into their metabolite product B. Altogether, the experimental data demonstrate that the replacement of the NHCHO substituent of compound A with a hydrophilic NHCH(CH(2)OH)(2) chain preserves the intact imide function that is known to be essential for topoisomerase I inhibition and cytotoxicity. The transformation of compound A into the anhydride metabolite B (or its diacid open form) occurs much more slowly compared to compound D. Half-life parameter t(1/2) of 67 and 245 min(-1) were calculated for compounds A and D, respectively. A molecular modeling analysis, performed to compare the conformation and electronic properties of compounds A and D, offers a rational explanation for the gain of chemical stability of the indolocarbazole derivative D. The data provide important information for the rational design of antitumor indolocarbazole derivatives.
Goossens
Jean-François
JF
Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, 59006 Lille, France.
Kluza
Jérôme
J
Vezin
Hervé
H
Kouach
Mustapha
M
Briand
Gilbert
G
Baldeyrou
Brigitte
B
Wattez
Nicole
N
Bailly
Christian
C
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism*; D004355:Drug Stability; D005960:Glucosides / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D010949:Plasma / Q000378:metabolism*; D014867:Water / Q000737:chemistry
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; D007211:Indoles; D014867:Water; C053339:rebeccamycin