149809-25-6Relevant articles and documents
The structure-activity relationships of A-ring-substituted aromathecin topoisomerase i inhibitors strongly support a camptothecin-like binding mode
Cinelli, Maris A.,Morrell, Andrew E.,Dexheimer, Thomas S.,Agama, Keli,Agrawal, Surbhi,Pommier, Yves,Cushman, Mark
scheme or table, p. 5535 - 5552 (2010/10/01)
Aromathecins are inhibitors of human topoisomerase I (Top1). These compounds are composites of several heteroaromatic systems, namely the camptothecins and indenoisoquinolines, and they possess notable Top1 inhibition and cytotoxicity when substituted at position 14. The SAR of these compounds overlaps with indenoisoquinolines, suggesting that they may intercalate into the Top1-DNA complex similarly. Nonetheless, the proposed binding mode for aromathecins is purely hypothetical, as an X-ray structure is unavailable. In the present communication, we have synthesized eight novel series of A-ring-substituted (positions 1-3) aromathecins, through a simple, modular route, as part of a comprehensive SAR study. Certain groups (such as 2,3-ethylenedioxy) moderately improve Top1 inhibition, and, often, antiproliferative activity, whereas other groups (2,3-dimethoxy and 3-substituents) attenuate bioactivity. Strikingly, these trends are very similar to those previously observed for the A-ring of camptothecins, and this considerable SAR overlap lends further support (in the absence of crystallographic data) to the hypothesis that aromathecins bind in the Top1 cleavage complex as interfacial inhibitors in a 'camptothecin-like' pose.
Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I
Luzzio, Michael J.,Besterman, Jeffrey M.,Emerson, David L.,Evans, Michael G.,Lackey, Karen,et al.
, p. 395 - 401 (2007/10/02)
The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7--10,11-(methylenedioxy)-(20S)-camptothecin trifluoroacetate (6) and 7--10,11-(ethylenedioxy)-(20S)-camptothecin trifluoroacetate (7) are described.The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to 0.003 mg/mL for camptothecin in the same buffer.In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan.In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM.Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.
