Synthesis of Inhibitors of Cystathionine β-Synthase

Date

2014-05

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Abstract

Hydrogen sulfide (H2S) is well known for its harmful effects to the environment, yet within the last decade evidence of its role as an endogenous gasotransmitter has surfaced. Both overproduction and underproduction of H2S can lead to detrimental health conditions; therefore, adequate metabolism of H2S is required to maintain homeostasis. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are the two main PLP-dependent enzymes that contribute to H2S metabolism through generation from L-cysteine. A recent study has discovered a link between CBS-derived H2S and tumor growth in colorectal cancer. Overproduction of H2S in colon cancer cells leads to an increase in ATP generation and development of new blood vessels, which are two factors required for tumor growth. Therefore, it is promising to develop potent and selective inhibitors of the CBS enzyme to serve as potential drug therapies for colorectal cancer. Aminooxyacetic acid (AOA) is an inhibitor of CBS, yet has a major limitation in that it is not selective and inhibits a variety of other PLP-dependent enzymes. To overcome this limitation, two AOA conjugates were synthesized in an attempt to deliver the inhibitor into the mitochondria. The use of the triphenylphosphonium cation should allow for the selective accumulation of AOA into the mitochondria due to the high inner membrane potential gradient. Modification of the carboxylic acid functionality of AOA to an ester and amide functionality will also allow for comparison to AOA inhibitor activity once tested in animals.
Another modification of AOA was made by converting the oxyamino functionality into a hydroxylamino functionality, in an effort to enhance the bioactivity and drug-properties of the compound. In addition, the CBS product, L, L-cystathionine, was modified by converting the amino group of the serine (or cysteine) derived half of the product into a carbonyl group, although purification was not successful. Both of the aforementioned modifications will allow for comparison to natural inhibitor and product binding activities, respectively.

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Keywords

Cystathionine β-synthase, Colorectal cancer, Aminooxyacetic acid

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