Recent developments in novel pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis and biological evaluation

Abstract

The biological activity of many low molecular weight antitumor compounds appear to be related to their mode and specificity of interaction with particular DNA sequences. Such small molecules are of considerable interest in chemistry, biology and medicine. Most of the anticancer drugs employed clinically exert their antitumor effect by inhibiting nucleic acid (DNA or RNA) or protein synthesis. Inhibition can occur for example through cross-linking of bases in DNA or binding to and inactivation of enzymes necessary for the synthetic processes. It is evident that DNA is an important cellular target for many anticancer agents. Much information has been obtained from molecular genetics, i.e. replication of DNA and its transcription to RNA, which provides the template for protein synthesis. DNA is a well-characterized intracellular target but its large size and sequential nature makes it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this context PBDs (pyrrolo[2,1-c][1,4]benzodiazepines), a group of potent naturally occurring antitumor antibiotics produced by various Streptomyces species, are one of the most promising types of lead compounds. They differ in the number, type and position of substituent in both their aromatic A-ring and Py C-rings, and in the degree of saturation of the C-rings which can be either fully saturated or unsaturated at either C2-C3 (endocyclic) or C2 (exocyclic). There is either an imine or carbinolamine methyl ether at the N10-C11 position. This latter is an electrophilic center responsible for alkylating DNA. In the search for compounds with better antitumor selectivity and DNA sequence specificity many PBD analogues have been synthesized in an attempt to increase their potency against tumor cells. We review here recent progress on pyrrolo[2,1-c][1,4]benzodiazepine (PBDs) analogues and their conjugates, also the progress and developments of PBD conjugates with polyamides (information reading molecules in the minor groove of DNA). For example, the cross-linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin and melphalan. A large number of PBD dimers and polyamide conjugates with varying linker lengths and bearing different heterocycles at different positions in the PBD ring synthesized in our group and their pharmacological properties have been reviewed.