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(l ,4)benzodiazepine Antitumor Antibiotics: Chemistry, Interaction with DNA, and Biological Implications
The pyrrolo(l,4)benzodiazepine (P(1,4)B) antitumor antibiotics, anthramycin, tomaymycin, sibiromycin and the neothramycins A and B, are potent anticancer agents that form covalent adducts through the exocyclic amino group of guanine in DNA. This review describes the chemistry important for both the DNA reactivity and synthesis of the carbinolamine containing drugs and the strategy for elucidation of the three-dimensional form of the adduct with DNA. The high DNA sequence specificity as well as some of the observed biological consequences of DNA damage caused by these agents in human and yeast cells are rationalized through the proposed structure of the drug-DNA adducts. Parallel toxicological studies have led to a proposal for the underlying mechanism for the cardiotoxicity of certain members of this group of agents. A rationale for designing drugs which should retain their potent antitumor activity without the associated cardiotoxicity is also proposed. Lastly, the application of the P(l,4)B's as probes for monitoring drug binding to DNA and drug-induced conformational changes is described.
Prothracarcin, a novel antitumor antibiotic.
A novel antibiotic, prothracarcin was isolated from the culture broth of Streptomyces umbrosus subsp. raffinophilus DO-62. The antibiotic has the molecular formula of C14H14N2O and belongs to the pyrrolo [1,4]benzodiazepine antibiotics. Its structure has been elucidated by mass and NMR spectra. It is active against Gram-positive and Gram-negative bacteria and experimental murine tumor sarcoma 180 and leukemia P388.