Design and synthesis of novel amino-substituted xanthenones and benzo[b]xanthenones: evaluation of their antiproliferative activity and their ability to overcome multidrug resistance toward MES-SA/D x 5 cells.
A number of new xanthenone and benzo[b]xanthenone amino derivatives and their pyrazole-fused counterparts have been designed and synthesized possessing structural analogy to the potent anticancer agent 9-methoxypyrazoloacridine. The synthesis of the compounds proceeds through nucleophilic substitution of 1-chloro-4-nitroxanthenone or the corresponding benzo[b]xanthenone by the appropriately substituted amine or hydrazine, reduction of the nitro group, and conversion into the suitable dialkylaminoacetamides. This method cannot be applied for synthesis of the pyrazole-fused benzo[b]xanthenones, consequently a different, simple, and high-yielding synthetic procedure was developed for the preparation of the target molecules. In vitro cytotoxic potencies of the new derivatives toward the murine leukemia L1210 cell line, human colorectal adenocarcinoma (HT-29), and human uterine sarcoma (MES-SA and its 100-fold resistant to doxorubicin variant MES-SA/D x 5) cell lines are described and compared to those of reference drugs. The compounds exhibited significant cytotoxic activity against the tested cell lines and in addition they retain activity against the multidrug resistant MES-SA/D x 5 subline, showing resistant factors close to 1. A number of derivatives were found to possess DNA binding capacity, according to a standard ethidium bromide displacement assay. The majority of the studied compounds induce a G2/M arrest, although among them some G1 or S blockers have also been identified.
Kostakis
Ioannis K
IK
Division of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
Pouli
Nicole
N
Marakos
Panagiotis
P
Skaltsounis
Alexios-Leandros
AL
Pratsinis
Harris
H
Kletsas
Dimitris
D
D000586:Amination; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011720:Pyrazoles; D014966:Xanthenes; C031280:pyrazole; D001554:Benzene