Anti-Cancer Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Michelle Prudhomme  
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France

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The Chemistry of Bisphosphonates: From Antiscaling Agents to Clinical Therapeutics

Author(s): Leo Widler, Wolfgang Jahnke, Jonathan R. Green.

Abstract:

In the early 1960s, inorganic pyrophosphate (PPi) was found to be present in body fluids and to act as a natural inhibitor of calcification by its interaction with hydroxyapatite. In addition to inhibiting the formation of calcium phosphate, PPi also inhibited dissolution of hydroxyapatite crystals, which made it interesting for pharmacologic applications in the treatment of diseases associated with excessive bone resorption. However, PPi is metabolically unstable because of rapid hydrolysis of the P-O-P backbone by hydrolytic enzymes in the gastrointestinal tract. In the search for more stable analogues of PPi, attention turned to the chemical class of bisphosphonates (BPs). The first BPs were synthesized in the 19th century and widely used for industrial applications. Bisphosphonates are formally derived from PPi by replacement of the bridging oxygen atom by a carbon atom, resulting in a P-C-P moiety that is resistant to hydrolysis. In addition to its decisive role in stability, the central carbon atom also provides an attachment point for 2 additional substituents (R1 and R2). While R1 is preferentially a hydroxy group, allowing such derivatives to act as powerful tridentate ligands for calcium (bone hook), R2 is mainly responsible for antiresorptive potency. The clinically available BPs can be divided into 2 subclasses based on their structure and molecular mechanism of action. The simple, non-nitrogen – containing derivatives can be incorporated into non-hydrolyzable cytotoxic ATP analogues. The more potent nitrogen-containing BPs inhibit FPPS, a key enzyme in the mevalonate pathway. Details of this crucial molecular interaction have recently been elucidated. Members of this class have a wide therapeutic window between therapeutic inhibition of bone resorption and undesired inhibition of bone formation, and several have found widespread use for the treatment of benign and malignant bone disease.

Keywords: Alendronate, Bisphosphonate, Farnesyl pyrophosphate synthase, Ibandronate, Pamidronate, Zoledronic acid, farnesyl pyrophosphate synthase (FPPS), nitrogen-containing BPs, geranyl pyrophosphate (GPP), Bisphosphonates

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Article Details

VOLUME: 12
ISSUE: 2
Year: 2012
Page: [95 - 101]
Pages: 7
DOI: 10.2174/187152012799014959
Price: $58