A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racemisation at the C11a-position during the cross-coupling reaction studied. Three library members (21, 30 and 33) were sufficiently cytotoxic in the NCI's preliminary screen to warrant further evaluation, and one (30, R=p-Br) was found to be cytotoxic at the sub-micromolar level in the A498 renal cancer cell line. DNA thermal denaturation studies suggested that this activity may be associated with non-covalent DNA interaction, and also demonstrated that introduction of C2-C3 unsaturation and addition of C2-aryl functionalities to the PBD dilactam skeleton significantly enhanced helix stabilisation compared to the unsubstituted PBD dilactam (6).
[Show abstract][Hide abstract] ABSTRACT: A 66-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) library has been successfully synthesized in parallel via Suzuki coupling using PS-PPh3Pd (catalyst) and PS-DEAM (scavenger) under microwave radiation. Library members were obtained in sufficient yield (up to 91%) and purity (85-98% crude) for biological evaluation.
[Show abstract][Hide abstract] ABSTRACT: The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a class of DNA minor groove binding agents that react covalently with guanine bases, preferably at Pu-G-Pu sites. A series of three fluorescent PBD-coumarin conjugates with different linker architectures has been synthesized to probe correlations between DNA binding affinity, cellular localization and cytotoxicity. The results show that the linker structure plays a critical role for all three parameters.
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