~ ~ ) TETRAHEDRON LETTERS Tetrahedron Letters 39 (1998) 6475-6478 Pergamon Aromatic Layered Guanidines Bind Sequence-Specifically to DNA Minor Groove with Precise Fit Ryuuta Fukutomi, * Aya Tanatani, * Hiroki Kakuta,: Nobuo Tomioka, ~ Akiko Itai, ~ Yuichi Hashimoto,* Koichi Shudo, * and Hiroyuki Kagechika *'~ tGraduate School of Pharmaceutical Sciences, Universityof Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and tlnstitute of Molecular and CellularBiosciences, Universityof Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, and ~Institute of Medicinal Molecular Design, 5-24-5 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Received 13 May 1998; revised 29 June 1998; accepted 30 June 1998 Abstract: Tetraguanidines (1 and 2) with an aromatic multilayered structure exhibit potent binding to a specific site of DNAs with binding constants of the order of 107 M ~ as deduced from Scatchard analysis of ultrafiltration data and simulation of CD titration curves. NMR spectra of the complexes indicated that 1 and 2 bind DNAs sequence-specifically at the minor groove, as predicted by computational docking studies. © 1998 ElsevierScienceLtd. All rights reserved. Keywordy. Guanidines; Nucleic acids; Molecular recognition; NMR Compounds that bind to double-stranded DNAs, in particular, sequence-specific binders, may modulate gone replication or transcription. L2 Minor groove binders are a typical class of noncovalent DNA-binders.3 Structurally, most of them consist of cationic functional groups such as amidino or guanidino groups at the terminal position(s) with a concatenated backbone of moderate planarity, as represented by netropsin, distamycin, and their synthetic analogs. The minor ~3 groove in typical B-DNA is narrow with a width of ~ \ ~'- N' C÷)~3NH 2 5.7 A and a depth of 7.5 ,~,4 but the pocket is large H3q ,.~-"~ +,/~'-NH2 enough to accommodate compounds rather b u l k i e r t h a n conventional minor H2 HI~/+I~~ gHH3 H2N--(N+ ~'~-'p CH3H3C" ~ N groove binders, as proved H3c,,N~ CH 3 by the side-by-side dimeric arrangement of distamycin 3c +N).__NH 2 '/%NH2 A in the groove,5 and the sequence-specific recognition H3C-"N~'~"~'I/~ ['X H3qN..~ N'CH3 by polyamide dimers or their hairpin-type derivatives. 6 / CH3 Based on the spatial size and the electronic properties H2~ H2N~N + of the minor groove, we selected the aromatic layered H3 c guanidines 1 and 2, so that one molecule would fit 1 2 precisely into the groove pocket. 0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PH: S0040-4039(98)01378-1