Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Abstract

CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder

“…In this study, we evaluated ICT2700, a chloromethylpyrroloindoline, which is rationalized to undergo CYP1A1-mediated oxidation resulting in production of an ultrapotent DNA alkylating cytotoxin. ICT2700 is a synthetic modification of the seco-duocarmycins as an approach to address the unmet clinical potential of this family of agents, which have failed to show an acceptable therapeutic index in clinical trials (17). We showed a significant increase in in vitro cytotoxicity of ICT2700 in RT112 (CYP1A1 positive) but not in EJ138 (undetectable CYP1A1) human bladder tumor cell lines.…”

“…17). We showed previously that CYP1A1 oxidation restores the hydroxyl group critical to the spirocyclization mechanism necessary for DNA alkylation ( Fig.…”

“…In our laboratory, we have previously identified the duocarmycin family of natural products (17) to possess a pharmacophore suitable for modification to create CYP-activated chemotherapeutic prodrugs (18). We have synthesized a truncated chloromethylpyrroloindoline (ICT2700), which we have shown to undergo CYP1A1-mediated oxidation, resulting in production of a potent and highly specific DNA minor groove alkylating agent (19).…”

Pseudomonas aeruginosa NfsB and nitro-CBI-DEI – a promising enzyme/prodrug combination for gene directed enzyme prodrug therapy

“…Also promising for GDEPT are the nitro-chloromethylbenzindolines (nitro-CBIs), originally designed to be hypoxia-activated prodrugs [9] of amino analogues of the cyclopropylindoline anti-tumour antibiotics, exemplified by CC-1065 and duocarmycin SA [10,11]. It has been shown that the Escherichia coli nitroreductase NfsB (NfsB_Ec) can reduce nitro-CBIs in an oxygen-independent fashion, generating highly cytotoxic metabolites that alkylate the N3 of adenine in the minor groove of DNA [12].…”

Natural Product-Based Drug Discovery

“…Both, duocarmycins and yatakemycin may lead to the development of other natural products [18]; an extract of the fruit from Xylopia aethiopica demonstrated an antiproliferative action on human cervical cancer cells [19], while extracts of the leaves of Brysocarpus coccineus have suggested their potential use in cancer chemotherapy [20].…”