Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives

Abstract

Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative.

Molecular docking and quantum mechanical studies on biflavonoid structures as BACE-1 inhibitors

“…http://autodock.scripps.edu). Literature review shows that AutoDock has offered several fruitful advantages in the field of drug design [35].…”

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

“…29–31 To prove that SM145 inhibits the molecular chaperone function of hsp90, we performed two types of luciferase refolding assays. The first was a pure protein assay, where hsp90 and necessary co-chaperones were incubated with heat-denatured luciferase.…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…This cytoprotective response is usually referred to as a heat shock response (HSR). Investigation of the SM145's mechanism showed that in contrast to the classic inhibitors, SM145 did not induce this HSR [26][27][28]. This successful discovery with SM145 drove the development of new molecules that were less hydrophobic and more potent than SM145.…”

“…Performing amino acid scans on three positions (i.e. Position I, II and III) a Gly, an L-Phe and a D-Phe or an N-Me amino acid, (Compounds 2-13, Table 1), McAlpine et al found that unlike previous work on pentapeptides [31,[41][42][43][44][45][46][47][48], the N-Me substituent was unable to lock the macrocycle into a single conformer (San B2-B4). In contrast, substitution with L-Phe or a D-Phe produced a single macrocyclic conformer (San B9, B10, B12 and B13).…”