Although the antibiotic lavendamycin is a potent antitumor agent, its clinical use has been precluded because of high toxicity. We have synthesized a large number of substituted lavendamycin analogs and various in vitro and in vivo antitumor screenings have been performed on a substantial number of these compounds. These tests have shown that a significant number of lavendamycins are highly active against a wide range of human cancer lines. We have found that compared to their simple quinolinedione analogs, the lavendamycins are much less toxic to animals and show a high degree of selective toxicity. It appears that the fi-carboline (CDE ring) moiety of the molecule plays an important role in conferring this selective toxicity. Our data also indicate the importance of the C-7 amino and the C-2' amides or esters in enhancing the molecular activity. Several of the lavendamycin analogs were selected by the NCI Developmental Therapeutics Program for the in vivo hollow fiber and xenograft mouse models assays. These compounds have been shown to have high maximum tolerated doses, strong activity in the hollow fiber assays and have been evaluated against a number of cancers in animals. A serious limitation for the in vivo antitumor studies of these compounds, however, has been their low water solubility. Thus, the major objective of this proposal is to synthesize a number of novel water soluble analogs with acid side arms to increase water solubility while retaining those functional groups critical for biologic activity. Our preliminary studies indicate that these soluble analogs may indeed be more potent antitumor agents than their corresponding insoluble analogs. In addition, the role of the reduction potential in the antitumor activity of the lavendamycins has not been assessed. Thus, the list of novel lavendamycins to be synthesized will also include analogs with zero, one, two, three or four substituents on the pentacyclic skeleton representing molecules with a wide range of reduction potentials. The second objective of the research is to determine the biological activity of these novel compounds. The new analogs as well as some available untested analogs will be submitted to three independent collaborating groups: the NCI for the activity against H 60 tumor cell lines; R.Abraham's group for clonogenic survival assays and DNA damage assessment and H.Bealrs group for the NQO1 reductase assays. Assessments will be made as to whether the biological activity of these compounds correlates with their reduction potentials as has been observed for the simpler quinones. The assays perfomed by the last two groups are designed to elucidate the mechanism(s) of action of the lavendamycins. Hopefully, these studies will clarify not only the roles that the structure and water solubility play in determining the antitumor activity of the lavendamycins, but also the mechnism of action of these potentially useful therapeutic anticancer agents.
| Behforouz, Mohammad; Cai, Wen; Mohammadi, Farahnaz et al. (2007) Synthesis and evaluation of antitumor activity of novel N-acyllavendamycin analogues and quinoline-5,8-diones. Bioorg Med Chem 15:495-510 |
