A novel approach to the synthesis of cytotoxic C2-C3 unsaturated pyrrolo[2,1-c]benzodiazepines (PBDs) with conjugated acrylyl C2-substituents.
A concise synthesis of three novel C2-C3 unsaturated pyrrolo[2,1-c][1,4]benzodiazepine analogues (18-20) containing conjugated acrylyl C2-substituents is reported that utilises Heck coupling to install the C2-acrylyl side chains. These analogues possess significant cytotoxicity according to the NCI 60-cell line screen with 18 surpassing anthramycin (1) in potency.
Pyrrolo[2,1-c][1,4]benzodiazepine as a scaffold for the design and synthesis of anti-tumour drugs.
Compounds that bind in the minor groove of DNA have found use in the experimental treatment of cancer and certain infectious diseases. Furthermore, agents which target and can recognize discrete sequences of DNA have the potential to offer selective therapies by modulating the activity of specific transcription factors or genes. For this reason, a number of sequence-selective DNA binding agents have been evaluated with a range of affinities and recognition fidelities. In this respect, the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are of interest as they bind to guanine residues in the minor groove with a preference for Pu-G-Pu sequences. A dramatic increase in cytotoxicity and sequence selectivity has been achieved by linking two PBD units to form PBD dimers as cross-linking agents on opposite DNA strands (e.g., interstrand cross-links). SJG-136 is currently undergoing Phase I evaluation in both the United States (through the NCI) and United Kingdom (through Cancer Research United Kingdom). This review will focus on design, synthesis and structure activity relationship studies of pyrrolobenzodiazepines as anticancer therapeutics reported since 2003.
Isolation and characterization of chromatin subunits.
Publisher Summary This chapter discusses methods used for isolation and characterization of chromatin subunits. Most reported physical studies of chromatin subunits have used more or less refined preparations of core particles. The particles are easily prepared in quantity because of their nuclease resistance and can be resolved to a fairly high degree of homogeneity. Studies of the entire repeating unit containing 200 base pairs of DNA have been inhibited by the fact that these structures are observed as intact entities only in the initial stages of digestion, and even then exhibit a rather broad heterogeneity in DNA size. This heterogeneity presumably results from the possibility that the first cleavage within spacer regions can occur at random over a range of sites and may be compounded by heterogeneity of spacer lengths. The techniques described in the chapter are employed for the isolation of core particles. If digestion conditions are carefully controlled, they can also be used for the preparation of small quantities of repeating units. Nuclease digestion of nuclei or chromatin with staphylococcal nuclease is discussed and isolation of core particle subunits and other nucleoprotein fragments is illustrated in the chapter.