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.
Search for new and novel chemotherapeutics for the treatment of human malignancies.
One of the hallmarks of cancer is the uncontrolled cell proliferation which causes more deaths among the human diseases throughout the globe. One in eight deaths worldwide are due to cancer, it is the second and third leading cause of death in economically developed and developing countries, respectively. As it is caused by both external and internal factors, a balanced approach to cancer control includes prevention, early detection, and effective treatment. In the treatment of cancer, chemotherapy is one of the practical methods and is widely used employing drugs that can destroy cancer cells by impeding their growth and reproduction. Despite the great strides made in the treatment of cancer over the past 50 years, it continues to be a major health concern and therefore, extensive efforts have been devoted to search for new scaffolds to develop chemotherapeutics. In this perspective, over the past two decades from this laboratory extensive efforts have been made in the development of new chemotherapeutic agents for the treatment of cancer. In this review, glimpses on types of current chemotherapeutic agents based on their action of inhibition and the new molecules that are being developed based on the scaffolds such as pyrrolo[2,1-c][1,4]benzodiazepines, podophyllotoxins, benzothiadiazine 1,1-dioxides, naphthalimides and monastrol across the world as well as in this laboratory have been articulated.
Studies on the mechanism of action of anthramycin methyl ether, a new antitumor antibiotic.
Summary Anthramycin methyl ether (AME), an antibiotic with antitumor activity, inhibits the in vivo and in vitro synthesis of RNA and DNA by Ehrlich ascites carcinoma cells. AME is a competitive inhibitor (with respect to DNA) of the cell-free synthesis of RNA and DNA by the DNA-dependent polymerase enzymes, as well as the enzymatic hydrolysis of DNA by DNase I. The interaction of AME with DNA was demonstrated by the isolation of an AME-DNA complex by gel filtration chromatography on Sephadex G-50 columns, by equilibrium dialysis studies, by ultraviolet absorption spectroscopy, by an increase in the melting temperature (Tm) of DNA when AME was added, and by the displacement of methyl green from a DNA-methyl green complex by AME. The DNA helix must be intact for AME to bind to DNA and for AME to inhibit the DNA-dependent enzymic reactions. These results are compatible with the proposition that AME exerts its actions as a growth inhibitor by interacting with helical, double-stranded DNA to form an AME-DNA complex, which in turn prevents DNA from participating as a template in the biosynthesis of RNA and DNA.