TY - JOUR
TI - Design, synthesis, and antiproliferative activity of some new pyrazole-fused amino derivatives of the pyranoxanthenone, pyranothioxanthenone, and pyranoacridone ring systems: A new class of cytotoxic agents
AU - Kostakis, I.K.
AU - Magiatis, P.
AU - Pouli, N.
AU - Marakos, P.
AU - Skaltsounis, A.-L.
AU - Pratsinis, H.
AU - Léonce, S.
AU - Pierré, A.
JO - Journal of Medicinal Chemistry
PY - 2002
VL - 45
TODO - 12
SP - 2599-2609
PB - 
SN - 0022-2623, 1520-4804
TODO - 10.1021/jm011117g
TODO - 6,12 dihydro 3 methoxy 9,9,12 trimethyl 6 (2 piperidin 1 ylethyl) 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridine;  6,12 dihydro 3 methoxy 9,9,12 trimethyl 6 (2 pyrrolidin 1 ylethyl) 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridine;  6,12 dihydro 9,9,12 trimethyl 6 (2 piperidin 1 ylethyl) 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridine;  6,12 dihydro 9,9,12 trimethyl 6 (2 pyrrolidin 1 ylethyl) 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridine;  6,9 dihydro 1 methoxy 9,9 dimethyl 6 (2 piperidin 1 ylethyl)pyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazole;  6,9 dihydro 1 methoxy 9,9 dimethyl 6 (2 pyrrolidin 1 ylethyl)pyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazole;  6,9 dihydro 9,9 dimethyl 6 (2 piperidin 1 ylethyl) (1)benzothiopyrano[4,3,2 c,d]pyrano[3,2 f]indazole;  6,9 dihydro 9,9 dimethyl 6 (2 piperidin 1 ylethyl)pyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazole;  6,9 dihydro 9,9 dimethyl 6 (2 pyrrolidin 1 ylethyl) (1)benzothiopyrano[4,3,2 c,d]pyrano[3,2 f]indazole;  6,9 dihydro 9,9 dimethyl 6 (2 pyrrolidin 1 ylethyl)pyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazole;  alcohol derivative;  antineoplastic agent;  cytotoxic agent;  diethyl [2 (6,12 dihydro 3 methoxy 9,9,12 trimethyl 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridin 6 yl)ethyl]amine;  diethyl [2 (6,12 dihydro 9,9,12 trimethyl 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridin 6 yl)ethyl]amine;  diethyl [2 (6,9 dihydro 1 methoxy 9,9 dimethylpyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazol 6 yl)ethyl]amine;  diethyl [2 (6,9 dihydro 9,9 dimethyl (1)benzothiopyrano[4,3,2 c,d]pyrano[3,2 f]indazol 6 yl)ethyl]amine;  diethyl [2 (6,9 dihydro 9,9 dimethylpyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazol 6 yl)ethyl]amine;  dimethyl [2 (6,12 dihydro 3 methoxy 9,9,12 trimethyl 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridin 6 yl)ethyl]amine;  dimethyl [2 (6,12 dihydro 9,9,12 trimethyl 9h pyrano[2,3 c]pyrazolo[3,4,5 m,n]acridin 6 yl)ethyl]amine;  dimethyl [2 (6,9 dihydro 1 methoxy 9,9 dimethylpyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazol 6 yl)ethyl]amine;  dimethyl [2 (6,9 dihydro 9,9 dimethyl (1)benzothiopyrano[4,3,2 c,d]pyrano[3,2 f]indazol 6 yl)ethyl]amine;  dimethyl [2 (6,9 dihydro 9,9 dimethylpyrano[3,2 f] (1)benzopyrano[4,3,2 c,d]indazol 6 yl)ethyl]amine;  ellipticine;  pyran derivative;  pyrazole derivative;  toluenesulfonic acid derivative;  unclassified drug, animal cell;  animal model;  antineoplastic activity;  article;  breast carcinoma;  cancer cell culture;  chemical reaction;  colon adenocarcinoma;  controlled study;  drug cytotoxicity;  drug design;  drug DNA binding;  drug synthesis;  human;  human cell;  leukemia L 1210;  lung adenocarcinoma;  mouse;  nonhuman;  RNA binding;  structure activity relation, Acridines;  Animals;  Antineoplastic Agents;  DNA;  Drug Screening Assays, Antitumor;  Fluorescence;  Humans;  Intercalating Agents;  Mice;  Structure-Activity Relationship;  Tumor Cells, Cultured;  Xanthenes
TODO - A series of novel pyranoxanthenones, pyranothioxanthenones, and pyranoacridones have been designed and synthesized as analogues of the acridone alkaloid acronycine, and their DNA binding and in vitro cytotoxicities have been investigated. The title compounds were derived by reaction of the corresponding 6-tosylates 5a-e with 2-hydroxyethylhydrazine, followed by conversion of the free hydroxyl of the substituted ethanols 6a-e to the corresponding mesylates, which were then treated with the suitably substituted secondary amines to provide the target derivatives 8-27. An alternative synthetic procedure for the preparation of these types of compounds is also developed, which resulted in an improvement of the overall yield. The new compounds exhibited interesting cytotoxic activity against the murine leukemia L1210 cell line, being more active than the parent compound, and a number of them possessed cytotoxicity against some human solid tumor cell lines. Especially in the case of a colon adenocarcinoma cell line, their IC50 values were comparable to that of mitoxantrone. The results of this study indicate that the incorporation of an amino-substituted pyrazole ring into the acronycine chromophore, or into its isosteres, results in an improvement of the lead compound's activity, and therefore, it may be of use in the search of new anticancer agents derived from this natural product.
ER -