149809-26-7Relevant 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.
Water soluble camptothecin derivatives
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, (2008/06/13)
The present invention relates to water soluble, camptothecin derivatives of formula (I), STR1 wherein: 1) R1 and R2 represent independently, hydrogen, lower alkyl, C3-7)cycloalkyl, C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; ii) R1 represents hydrogen, lower alkyl, C3-7)cycloalkyl, C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or lower alkoxy lower alkyl, and R2 represents --COR3, wherein: R3 represents hydrogen, lower alkyl, perhalo-lower alkyl, C3-7)cycloalkyl, C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy or lower alkoxy lower alkyl; or iii) R1 and R2 taken together with the linking nitrogen form a saturated 3 to 7 atom heterocyclic group of formula (IA) STR2 wherein: Y represents O, S, SO, SO2, CH2 or NR4 wherein: R4 represents hydrogen, lower alkyl, perhalo lower alkyl, aryl, aryl substituted with one or more lower alkyl, lower alkoxy, halogen, nitro, amino, lower alkyl amino, perhalo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl groups or; --COR5, wherein: R5 represents hydrogen, lower alkyl, perhalo-lower alkyl, lower alkoxy, aryl, aryl substituted with one or more lower alkyl, perhalo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl groups or; the pharmaceutically acceptable salts thereof; their use in the treatment of tumors and methods of their preparation.
Preparation of water soluble camptothecin derivatives
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, (2008/06/13)
The present invention relates to the synthesis of water soluble, camptothecin derivatives of formula (I), STR1 wherein: n represents the integer 1 or 2; R1 represents independently, hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; and R2 represents hydrogen and the pharmaceutically acceptable salts thereof.
