In general, the inventions described herein relate to rocaglate compositions, methods for making rocaglates, as well as their usage as therapeutic agents. Accordingly, there is a continuing need for development of new rocaglates as therapeutic agents and synthetic methods needed to prepare these new compounds. In addition, expansion of SAR studies requires procurement of novel compounds. In order to allow for broader evaluation of rocaglates as therapeutic agents, new methods for their preparation are urgently needed. Replacement of the tertiary hydroxyl with other substituents is an approach expressed in the literature for furthering SAR studies but has been frustrated by the difficulty in achieving chemical modification of this scaffold position.
Recently, Iwasaki and coworkers determined the co-crystal structure of rocaglamide bound to a human eIF4A-polypurine RNA complex which, among the interactions identified, was hydrogen bonding between the C8a tertiary hydroxyl of rocaglamide and N7 of a purine RNA base. In particular, the C8a tertiary hydroxyl has been shown to be critical which appears to be related to its role as a hydrogen bond (H-bond) donor alkylation of this tertiary hydroxyl completely eliminates cytotoxicity. Additionally, silvestrol has antitumor activity in a variety of pre-clinical murine cancer models including hematological and solid tumor types.Ĭhemical syntheses of cyclopentabenzofuran natural products and analogues have revealed structure-activity relationships (SAR) for antineoplastic activity in cancer cell lines leading to improved activity. For example, the rocaglate congener silvestrol was found to inhibit the eIF4F complex by interfering with the function of the DEAD box RNA helicase eIF4A (SEQ ID NO: 1). These natural products exhibit many interesting biological activities including the inhibition of the eukaryotic translation apparatus. In the last several decades, numerous chemical syntheses of rocaglates have been reported due to their intriguing structures. Since this time, over thirty natural products of the rocaglate family have been discovered sharing a highly substituted cyclopentabenzofuran with five contiguous stereocenters. In 1982, the first rocaglate was isolated from dried roots and stems of Aglaia elliptifolia Merr. is a large genus of angiosperm plants containing more than 120 species. In particular, there is significant interest towards the development of a family of compounds collectively known as rocaglates (flavaglines), a family of natural products found in plants of the genus Aglaia.Īglaia Lour. Small molecules targeting the translation machinery show considerable promise in the treatment of a variety of human maladies including cancer, viral infection, and neurodegeneration. Accordingly, aberrant translational control is associated with several pathological disorders. Regulation of translation is critical to a wide variety of biological processes, including cellular growth, survival, differentiation, and development. Translation is an essential step in the gene expression pathway that enables cells to make rapid and spatiotemporal alterations to the proteome. The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.
More particularly, the invention is directed to rocaglate compositions, their syntheses, and uses. This invention relates to rocaglate (flavagline) derivatives.
The Government has certain rights to the invention. DK088787 and GM118173 awarded by the National Institutes of Health. This invention was made with Government Support under grant Nos. 12, 2019, the content of which is incorporated herein by reference in its entirety. This application claims benefit under 35 U.S.C.