Experimental Oncology 24, 173-179, 2002 (September) 173 Nitrogen mustards (mustines) containing the estab- lished anticancer functionality N, N / -bis(2-chloro- ethyl)amino group, best represented by mechlore- thamine (HN 2 ), cyclophosphamide (Fig. 1, Structure A), ifosphamide, chlorambucil, melphalan etc [1] are im- portant alkylating agents. However in spite of their wide application in the management of several human tu- mors they have undesirable side effects. Hence efforts are ongoing to develop new mustine derivatives pos- sessing better therapeutic efficacy and lower toxicity [2]. Although various other structural patterns have been used as the carrier molecules for mustine group, naph- thalimide ring has not yet been explored, to our know- Received: August 16, 2002. *Correspondence. Fax : +91-33-475-7606; E-mail : usanyal@rediffmail.com Abbreviations used: FU  fluorouracil; BUN  blood urea nitro- gen; MST  median survival time; Napromustine  2-[3-{bis(2- chloroethyl)amino}propyl]-1H-benz[de]isoquinoline-1,3-dione; SAKP  serum alkaline phosphatase; SGOT  glutamic oxalo- acetic transaminase; SGPT  glutamic pyruvic transaminase. ledge. This structural pattern is particularly interesting since some substituted naphthalimides containing N-(2,2-dimethylaminoethyl) chain have demonstrat- ed substantial antineoplastic activity in various tumors [3]. To that group belongs Amonafide and Mitonafide (Fig. 1, Structure B) which inhibit DNA and RNA syn- thesis, intercalate DNA and exhibit substantial antican- cer activities in various animal tumors [4]. At present time those compounds are undergoing clinical trials [5]. Based on the above consideration and the results of our drug development program describing another potential anticancer compound Napro-NU [6], it is thought worth to investigate the compound of the gene- ral Structure C described in Fig. 1. We describe herein the synthesis through known route (Fig. 1, Structure 1), anticancer and toxicological evaluation of the new mus- tine compound Napromustine, 2-[3-{bis(2-chloro- ethyl)amino}propyl]-1H-benz[de]isoquinoline-1,3-di- one. It is hypothesised that upon in vivo enzymatic de- gradation it may exert synergistic activity since the naphthalimide ring residue may bind with DNA while EVALUATION OF NAPROMUSTINE, A NITROGEN MUSTARD DERIVATIVE OF NAPHTHALIMIDE, AS A RATIONALLY DESIGNED MIXED-FUNCTION ANTICANCER AGENT A. Pain 1 , S. Samanta 1 , S. Dutta 1 , A.K. Saxena 2 , M. Shanmugavel 2 , H. Kampasi 2 , G.N. Qazi 2 , U. Sanyal 1, * 1 Chittaranjan National Cancer Institute, Calcutta 700026, India 2 Regional Research Laboratory, Jammu-Tawi 180001, India ¨˙¯˝¨¯ ˇ—˛¨´˛˛ˇ˛¸¯´ ´˛´ ˝ˇ—˛¨˝, ¨˝¯˙¨—˛´˝˝˛ˆ˛ ˝ ˛˝˛´¯ ˝¸¨¨˜ . ˇØ 1 , .  1 , . ˜ 1 , .˚. Œæ 2 , . ªº 2 , ˆ. ˚æL 2 , ˆ.˝. ˚L 2 , . üº 1, * 1 ˝LºüßØ ŒßØ LæL Lü, ˚ºüŒ, ¨L 2 ˛Æºæ ¨ææººüæŒ ºÆL, ˜L-L, ¨L Napromustine, a new nitrogen mustard of substituted naphthalimide, has been synthesized as a new mixed-function anticancer agent from N-(3-bromopropyl) naphthalimide. Chemical alkylating activity of Napromustine exceeded that of N-di(2-chloroethyl)amine as a standard alkylating compound. Napromustine has displayed an excellent and reproducible antitumor activity in vivo against Sarcoma-180 and Ehrlich ascites carcinoma comparable to that of fluorouracil judging by the increase in median survival times of treated animals. Napromustine also significantly increased the life span of mice bearing highly advanced tumors for 10 days before the drug challenge. The com- pound under study did not affect hematopoiesis or induce hepatotoxicity and nephrotoxicity. This compound inhibits the synthesis of DNA and RNA in S-180 tumor cells. Meanwhile in vitro screening in 3 different human tumor cell lines did not reveal any significant cytotoxic activity. Key Words: anticancer agent, screening, alkylating activity, mustine derivative. ˝ æ N-(3-ÆLº)ºLL ŒŒ Læıª Œ Æߺ æLL L Læß  æL, ƺøLØ Æº ßæŒØ ºŒLºLøØ ŒLæü,  æßØ ºŒLºLøLØ  N-L(2-ıºLº)L. ˇLıºßØ Œ  L LæºüLL l æŒß-180 L æLª Œ ºLı Œºæ Æº ßæŒL,   ºLº. ´L æL   Lı æŒı LŒL ıºL LLº Œ æøæ ºLL Lß ßLæL Lßı- ıºæLºØ. ˇ  ªº ŒL ŒL,  ƺº ª- L ŒæLæü L LªLÆLº æL ˜˝˚ L —˝˚  ŒºŒı S-180. ´    L LæßLı in vitro  3 ºLßı Lßı ºLLı ŒºŒ ıºØ ºŒ   ºº LŒæLæŒª Œ. ˚ºß æº: Lıº æLL, æŒLLª, ºŒLºLø ŒLæü, L ºLL.