A series of compounds related to the macrocyclic portion of the DNA-damaging antitumor agent leinamycin were prepared as tools to characterize noncovalent DNA binding by this natural product. Acyclic (Z,E)-dienes were assembled via a Sonogashira coupling followed by partial hydrogenation. A Stille coupling was used in the cyclization step leading to a macrocyclic thiazole–diene analogue. Results obtained using the synthetic analogues reported here indicate that the extended π-system on the `left-hand side' of leinamycin is required for noncovalent association of the natural product with duplex DNA.