Evaluation of 8-Arylsulfanyl, 8-Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90

Abstract

Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC(50) = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.

Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects

“…a-e, determined as described in refs. 15,19,[45][46][47], respectively. C, complementation of Hsp90/p23 split RL reporter was orientation specific.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…However, development of this agent has been stunted by limited drug solubility and potency in the setting of frequent and diverse toxicities. Therefore, recent efforts in this arena have shifted toward clinical trials using lower 17-AAG doses in combination with conventional chemotherapeutic agents, or to the identification of novel Hsp90 inhibitors with improved potency and therapeutic indices (Llauger et al 2005). For example, IPI-504 is a novel, water-soluble Hsp90 inhibitor in clinical development that is converted to 17-AAG in vivo; this may enable targeted delivery of higher doses into tumor tissue (http://www.ipi.com).…”

HSP90 and its inhibitors (Review)

“…Another compound of this library, PU24FCL exhibits antitumor activities in both in vitro and in vivo models of cancer (122). Subsequently, several 8-arylsulfanyl, -sulfoxyl and -sulfonyl adenine derivatives of the PU-class were synthesized and retain the activity of the methylene linker compounds (X3=CH2) and are also chemically flexible which allows for extensive SAR studies (123). Recently, two research groups disclosed the 8-(phenylsulfanyl) purine series with ionizable groups appended at the end of the N(9) substituents, which showed improved oral bioavailability and measurable antitumor activity (124,125).…”