Monatshefte fu ¨r Chemie 138, 573–577 (2007) DOI 10.1007/s00706-007-0644-z Printed in The Netherlands Synthesis of a C-2 Stapled Bis-Lexitropsin Naim H. Al-Said 1; and Sami Klaib 2 1 Department of Applied Chemical Sciences, Faculty of Science, Jordan University of Science and Technology, Irbid, Jordan 2 Department of Chemistry, Tafila Technical University, Tafila, Jordan Received November 21, 2006; accepted (revised) December 4, 2006; published online May 2, 2007 # Springer-Verlag 2007 Summary. A convenient synthesis method was developed for the preparation of C-stapled homodimeric bis-lexitropsins connected through the nitrogen atoms of the central pyrrole ring with a bis-methylene linker. This lexitropsin is designed as a standard for other bis-lexitropsins with longer chains in biological evaluation and NMR studies. The key step in this method is the treatment of ethyl 4-nitropyrrole-2-carboxylate with flame-dried potassium carbonate in DMF followed by the addition of 1,2-dibromoethane to form the 1,2-dipyrroloethane derivative. Keywords. Synthesis; Homodimeric; Bis-lexitropsin; Minor groove. Introduction Understanding the interactions of double helical DNA with small molecules at the molecular level is crucial in designing new chemotherapeutic antibio- tic, antitumor, and antiviral drugs [1, 2]. Distamycin (1) is a well-studied member of the crescent-shaped pyrrolocarboxamides family of the naturally occur- ring oligopeptide antibiotics that binds reversibly in the minor groove of double-helical B-DNA at regions with at least four adjacent AT base pairs [3–5]. The high cytotoxicity of these compounds disqualifies them from being used as drugs. However, this class of pyrrole polyamides has been used as DNA se- quence selective vehicles for the delivery of alkylating agents to DNA targets [6–8]. Structural modifications by replacement of pyrrole by other heterocycles re- sulted in designing a novel class of minor groove binding agents called lexitropsins, i.e. ‘‘information reading molecules’’ [11–14]. Recent NMR studies have confirmed that the minor groove can accom- modate two peptidic lexitropsins stacked side-by- side in an antiparallel fashion filling the minor groove of the DNA [15–19]. As a consequence, two types of bis-lexitropsin structures have been de- signed: a hairpin, in which the two oligopeptides units are covalently linked in head-to-tail fashion by a linker [20–22], and cross-linked (stapled-lexitrop- sins), where the central rings of the two oligopep- tides are linked via a polymethylene chain [23–26]. These bis-lexitropsins recognize longer DNA se- quences with stronger binding affinity and higher specificity compared with the monomer when the linker has the appropriate length. Previously, we have reported the synthesis of cross-linked bis-lexi- tropsins 2 connected through the nitrogens of the cen- tral pyrrole ring with polymethylene chains (CH 2 ) n of different lengths (2, n ¼ 3–10) [23–25]. Moreover, recently we have accomplished a practical synthesis route to a terminally linked homodimeric bis-dis- tamycin analog [27]. However, several attempts to prepare stapled lexitropsins with a very short linker (3, n ¼ 2) were unsuccessful so far.  Corresponding author. E-mail: naim@just.edu.jo