Design, Synthesis, and Evaluation of a Radicicol and Geldanamycin Chimera, Radamide

Abstract

A chimera composed of the natural products radicicol and geldanamycin has been prepared through an amide linkage connecting the resorcinol moiety of radicicol to the quinone ring of geldanamycin. The inhibitory activity of these compounds was determined by their ability to inhibit Hsp90's inherent ATPase activity along with degradation of the Hsp90 client protein, HER-2 in MCF-7 breast cancer cells. [reaction: see text]

Hsp90 as a Target for Drug Development

“…It is proposed that such compounds will provide a succinct method for the elucidation of structure-activity relationships for both natural product inhibitors. Hybridized molecules such as radamide HQ, [78] radester HQ, [79] and radanamycin [80] have been synthesized and evaluated against several cancer cell lines, as described in Figure 9. The conformationally constrained macrocyclic chimeric compound radanamycin proved to be most active.…”

Propionate Analogues of Zearalenone Bind to Hsp90

“…Biological testing showed several of the analogues to be comparable in cytotoxicity with zearalenone (10). Thus, the five compounds ent-35, ent-34, 35, 42, and ent-42 displayed IC 50 values in the low mm range.…”

“…Indeed, radamide (5) compared well with geldanamycin (IC 50 = 5.9 mm vs. 2.5 mm for 1). [10] A related hybrid connecting the aryl rings via an ester bond was termed rad-A C H T U N G T R E N N U N G ester (6). [11] In cell proliferation studies (MCF-7 cells) IC 50 values in the low mm range were obtained.…”

Radanamycin, a macrocyclic chimera of radicicol and geldanamycin

“…5 A simple disconnection across the apex of each natural product, followed by hybridization of the RDC resorcinol moiety with the GDA quinone, afforded the macrocyclic compound. Previously, we reported the syntheses and inhibitory activities of the open chain chimeras of RDC and GDA (radester and radamide) 14,15 and based on their activities proposed that the conformationally constrained macrocyclic analogue would be more effective as entropic penalties would be minimized. In this letter, we report the synthesis and evaluation of radanamycin (1), a macrocyclic chimera of radicicol and geldanamycin.…”

“…1 H NMR of 9 provided evidence for a bent conformation similar to that observed for the natural products bound to Hsp90 by virtue of the upshield shift and anisotropy of several aliphatic protons. In analogy to the method used for the construction of the seco-agents, radester and radamide, 14 with in situ generated trimethylsilyl iodide to give hydroquinone 1. 17 With radanamycin in hand, we sought to determine its ability to inhibit Hsp90 as determined by the degradation of Hsp90-dependent client proteins.…”