Design, Synthesis, and StructureActivity Relationships for Chimeric Inhibitors of Hsp90

Abstract

Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

“…HSP90 has a prominent role in folding and conformational regulation of many proteins ranging from kinases to transcription factors [2][3][4]. The extensive list of HSP90 client proteins includes the proinflammatory kinase Akt [5][6][7][8][9][10][11]. Dissociation of HSP90 from its client proteins is associated with client protein degradation [2].…”

Recent Advances in Macrocyclic Hsp90 Inhibitors

“…Intriguingly, the iodo-resorcinol derivative 23b was found to be the most potent analogue. 121 For the radanamycin series, exemplified by macrocycle 24, a carbon chain linker of three carbons connecting the reduced hydroquinone to the bottom phenyl moiety on the left side, and a two carbon chain on the right side were optimal, giving comparable potencies to the radester analogues (Figure 2.11). 121 …”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…Thus, compounds with high antiproliferative activities and abilities to inhibit Hsp90-dependent protein degradation that are potential agents to cure cancer (Scheme 1) [4] are obtained in synthesis of radamicine (1a) and its seco analogues (1b-i) that represent series of macrocyclic chimeras radicicol (2) and geldanamycin (3) that are strong inhibitors of the Hsp90 N-terminal ATP-binding -macroamidation of acyclic precursors (4a-i) under the action of HATU and oxidation of the resulting hydroquinones (5a-i) into appropriate quinones (6c-i) (Scheme 1).…”

“…Thus, in target synthesis of biologically active macroheterocycles, after the stage of the formation of unsaturated cycles, the reaction of reduction of multiple bonds follows: exhaustive hydrogenation of C≡C, C=C and C=N bonds over Wilkinson's catalyst, Raney nickel and Pd/C, [6][7][8][9][10][11] reduction of C=N bonds using NaBH 4 or LiAlH 4 [6][7][8][9][10][11][12] and partial hydrogenation of the C-C triple bond to Z-double over Lindlar catalyst [13][14][15][16][17][18] that allow obtaining both isolated bonds, and conjugated systems.…”