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.

• Authors: Laura Llauger, Huazhong He, Joungnam Kim, Julia Aguirre, Neal Rosen, Ulf Peters, Peter Davies, Gabriela Chiosis
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 8 Pg. 2892-905 (Apr 21 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15828828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 9-(pent-4-ynyl)-8-(6-bromobenzo(1,3)dioxol-5-ylsulfanyl)adenine
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Sulfones
• Sulfoxides
• Adenine

Topics

• Adenine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding, Competitive
• Cell Line
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Mice
• Structure-Activity Relationship
• Sulfones (chemical synthesis, chemistry, pharmacology)
• Sulfoxides (chemical synthesis, chemistry, pharmacology)