Sioorganic & Medici& zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Chemistry Letters, Vo1.3. No.12. pp. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC 25112514.1993 Printedin Great Britain 0960-894X93 $6.00 + .OO 0 1993 Pqamon Press Ltd zyxwvutsrqponmlk Synthesis and Antitumor Activity of a New Class of Pyrazolo[4,3-e]pyrrolo[l,2-a][l,4]diazepinone Analogs of Pyrrolo[ 1,4] benzodiazepines (PBDs) Pier Giovanni Baraldi*a, Albert0 Leonib, Barbara Cacciaria, Stefano ManfredinP, Daniele Simonia zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM ‘D@ artimento di Scienze Fmceurikhe, Universitidi Ferrara, Via Fossato di Mortara 17-19, 144100 Fewara, Italy b Dipartimento di S&rue Formaceutiche, Univmit~ di Bologna, Via Belmeloro 6, 1-40126 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCB BOlO& ?M, hkl. (Received in Belgium 7 April 1993; accepted 1 August 1993) Key words: anthramycin, pyraz0lo~4.3-elpyrrolo[l~-al[l.4]diazep analogs, antitumor activity. synthesis. Abshoct: A new class of Pyrrolo[l~4lbenzodiazpines (PBDs) analogs featuring apyrazolo[4,3-e]pyrrolo[l~~)[l.4]~~ ring system has been designed and synthesizexl. In these compounds the A-benzene ring, character&tic of PBDs, has been replaced by a dimethylpyrazole ring, a modification suggested by mcdelling studies performed on the PBD base structure. Biological evaluation revealed appreciable antitumor activity for compounds 14 and 15 (8.84-22.4 PM) which encourages further investigation of the e or N7 alkyl pyrazole analogs. Pyrrolo[ 1,4]benzodiazepines (PBDs) are potent antitumor antibiotics derived from various Streptomyces species showing interesting properties from both synthetic and biological standpoir&. Natural products belonging to this family include Anthramycin. Tomaymycin, Neothramycins A and B, Sibiromycin and Chicamycin. The antitumor activity of these natural products is believed to involve the formation of a labile covalent aminal linkage between the carbinolamine carbon (Cl 1) of the antibiotics and the 2-amino group of guanine residues within the minor groove of DNA2. Reaction with guanines in specific sequences results in DNA sequence specificity. The resulting DNA-antibiotic adduct inhibits DNA replication. 2511