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.
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 IC(50) 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.
Kostakis
Ioannis K
IK
Division of Pharmaceutical Chemistry and Pharmacognosy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
Magiatis
Prokopios
P
Pouli
Nicole
N
Marakos
Panagiotis
P
Skaltsounis
Alexios-Leandros
AL
Pratsinis
Harris
H
Léonce
Stephane
S
Pierré
Alain
A
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005453:Fluorescence; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014966:Xanthenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D014966:Xanthenes; D004247:DNA