Evaluation of fluoren-NU as a novel antitumor agent.

ABSTRACT

A new nitrososourea derivative, namely fluoren-NU, 3-[2-(3-(2-chloroethyl)-3-nitrosouriedo}ethyl]-spiro[5,9'-fluorenyl]imidazolidine-2,4-dione (compound 2e), was synthesized from 3-(2-bromoethyl)-spiro [5,9'-fluorenyl]imidazolidine-2,4-dione via a four-step synthetic procedure. Its chemical alkylating activity was assessed by coupling with 4-(4-nitrobenzyl)pyridine. In vitro screening in six human tumor cell lines, namely SK-N-SH CNS, IMR-32 neuroblastoma, A549 lung, DU-145 prostate, HL-60 leukemia, and U-937 lymphoma, revealed its significant cytotoxicity in SK-N-SH. Its in vivo antitumoral potency was assessed in murine ascites tumors Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180) by measuring the increase in median survival times (MST) of drug-treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in both of these tumors. Life span of mice bearing advanced tumor for 5 days before the drug challenge was also considerably increased. In vivo toxicological assay at its optimum dose of 40 mg/kg for days 1-7 treatment schedule was conducted sequentially on day 9, 14, and 19 in normal and EAC-bearing mice. Results revealed that it did not adversely affect hematopoiesis or exhibit drug-induced hepatotoxicity and nephrotoxicity. It has shown minimal cytotoxic effect on human peripheral blood mononuclear cells (PBMC) having a high IC50 value of 792 microM. Compared to Mitonafide and CCNU used as standards it also significantly inhibited DNA and RNA synthesis in EAC tumor cells in vitro at 8 microM concentration.