149809-26-7

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Relevant academic research and scientific papers

The structure-activity relationships of A-ring-substituted aromathecin topoisomerase i inhibitors strongly support a camptothecin-like binding mode

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

The present invention relates to water soluble, camptothecin derivatives of formula (I). wherein A represents a moiety of the formula (IIA), (IIB) or (IIC): X is selected from the group consisting of alkyl, aryl, (CH2)mOR1, (CH2)mSR1 and (CH2)mNR1R2 wherein m is an integer of 0 to 6, and R1 and R2 are hydrogen, lower alkyl, aryl or together with the nitrogen form a 5-7 membered ring; q is an integer of 0 to 2; n represents the integer 1 or 2; p is an integer of 1 to 6; Y and W are selected from the group consisting of alkyl, aryl, alkoxy, aryloxy and amino, Q is oxygen or sulfur; P is phosphorus; J represents the atoms necessary to complete a 5 or 6 membered aromatic ring; and the pharmaceutically acceptable salts thereof; their use as topoisomerase inhibitors, their preparation; and their use in the treatment of cancer.

Water soluble camptothecin derivatives

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.

Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I

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.

Preparation of water soluble camptothecin derivatives

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.