845863-22-1Relevant academic research and scientific papers
Synthesis and evaluation of the apoptosis inducing and CT DNA interaction properties of a series of 4β-carbamoyl 4′-O- demethylepipodophyllotoxins
Sang, Chun-Yan,Liu, Jian-Fei,Qin, Wen-Wen,Zhao, Jie,Hui, Lin,Jin, Yong-Xin,Chen, Shi-Wu
, p. 59 - 67 (2013)
A series of carbamate derivatives of 4′-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-4′-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.
Synthesis and biological study of a new series of 4′- demethylepipodophyllotoxin derivatives
Duca, Maria,Guianvarc'h, Dominique,Meresse, Philippe,Bertounesque, Emmanuel,Dauzonne, Daniel,Kraus-Berthier, Laurence,Thirot, Sylvie,Léonce, Stéphane,Pierré, Alain,Pfeiffer, Bruno,Renard, Pierre,Arimondo, Paola B.,Monneret, Claude
, p. 593 - 603 (2007/10/03)
Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4′-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4β-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4′-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.
