Samanta S., Pain A., Ghosh M., Dutta S., Sanyal U.

Aim: To develop a rationally designed new nitrogen mustard namely Fluorenhymustine (compound 2), where N,N'-bis(2-chloroethyl)amino group, the established anticancer functionality, is attached to the 2-ethyl fluorenone hydantoin moiety. Materials and Methods: Starting from fluorenone hydantoin, a 3-step synthetic procedure was followed to obtain the title compound. 4-(4-Nitrobenzyl)pyridine was used to assess its chemical alkylating activity. Murine tumors (Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180)) were used to assess its in vivo activity. Its cytotoxicity was determined in vitro in MCF-7 human breast tumor cell line, toxicity - in vivo in normal and EAC bearing mice. 3H-Thymidine and 3H-Uridine were employed to study its inhibitory effect on DNA and RNA synthesis respectively in S-180 tumor cells in vitro. Results: Alkylating activity of fluorenmustine exceeded that of N-di(2-chloroethyl)amine used as a standard alkylating compound. It has displayed an excellent and reproducible antitumor activity in vivo against EAC and S-180 comparable to that of 5-fluorouracil judging by the increase in median survival times of treated animals. It also significantly increased the life span of mice bearing advanced tumors for 6 days before the drug challenge. However in vitro screening in MCF-7 did not reveal any significant cytotoxicity. The compound did not adversely affect hematopoiesis at its optimum dose. Drug-induced hepatotoxicity and nephrotoxicity were also not detected. It inhibited the synthesis of DNA and RNA in S-180 tumor cells at 8 M concentration. Conclusion: Results indicated promising chemotherapeutic potential of Fluorenhymustine.

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