Structural Elaboration of a Natural Product: Identification of 3,3′‐Diindolylmethane Aminophosphonate and Urea Derivatives as Potent Anticancer Agents

Abstract

An approach involving rational structural elaboration of the biologically active natural product diindolylmethane (DIM) with the incorporation of aminophosphonate and urea moieties toward the discovery of potent anticancer agents was considered. A four-step approach for the synthesis of DIM aminophosphonate and urea derivatives was established. These novel compounds showed potent anticancer activities in two representative kidney and colon cancer cell lines, low toxicity to normal cells, higher potency than the parent natural product DIM and etoposide, and potent inhibition of cancer cell migration. Biophysical and immunological studies, including DAPI nuclear staining, western blot analysis with apoptotic protein markers, flow cytometry, immunocytochemistry, and comet assays of the two most potent compounds revealed good efficacies in apoptosis and DNA damage. It was found that down-regulation of nuclear factor κB (NF-κB p65) could be an important mode of action in apoptosis, and the two most potent derivatives were found to be more potent than parent compound DIM in the down-regulation of NF-κB. Our results show the importance of structural elaboration of DIM by rational incorporation of aminophosphonate and urea moieties to produce potent anticancer agents; they also suggest that this approach using other structurally simple bioactive natural products as scaffolds holds promise for future drug discovery and development.

Brønsted Acid Catalyzed Bisindolization of α‐Amido Acetals: Synthesis and Anticancer Activity of Bis(indolyl)ethanamino Derivatives

“…However, the reduction of the nitro group to the corresponding free amine was found to be difficult, and in situ acylation derivatization was needed. Yet, although all of these synthetic strategies are useful, they have some limitations in terms of the requirement for stoichiometric amounts of promoters or activators (e.g., Lewis or Brønsted acids), and/or the deprotection step is low yielding and limited by poor functional‐group tolerance 12. Consequently, the development of new, catalytic and efficient methods to broaden the substrate scope and enhance the selective construction of such molecules is highly desirable.…”

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

“…1,2 Many times, structurally derived compounds have been found to interact with a new molecular target, rather than an original one. Podophyllotoxin is tubulin polymerization inhibitor, 3 whereas its synthetic derivative etoposide is a topoisomerase II-inhibitor (TopoII).…”

FOXM1-mediated downregulation of uPA and MMP9 by 3,3′-diindolylmethane inhibits migration and invasion of human colorectal cancer cells

“…DIM is considered to be a promising natural cancer preventive agent. Although DIM has been proven to impart antitumor effects on numerous cancers both in vitro and in vivo (4)(5)(6)(7)(8)(9)11,13,(15)(16)(17)(18)(19), its antimetastatic effects in colorectal cancer and the underlying mechanism have not been fully elucidated. In the present study, we demonstrated that DIM inhibits the migration and invasion of colorectal cancer cells by inactivation of FOXM1 and subsequent downregulation of uPA and MMP9.…”

“…The cancer preventive role of 3,3'-diindolylmethane (DIM) in several types of cancer cells has been highlighted, and several studies have proposed DIM as a potent natural dietary compound that reduces colorectal cancer risk and performs several antitumor activities (4)(5)(6)(7)(8)(9)(10)(11). These functions include inhibition of colorectal cancer cell proliferation by suppression of YAP through an Akt-dependent process, alteration of cell cycle progression, and activation of caspase-8 to induce apoptosis (6,10,11).…”