Diazirines. II. Synthesis and properties of small functionalized diazirine molecules. Observations on the reaction of a diaziridine with the iodine-iodide ion system

Church, Robert F.; Weiss, Martin J.

doi:10.1021/jo00833a001

Cited by 109 publications

(73 citation statements)

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“…3-Azibutan-1-ol was synthesized as previously reported (20). All other reagents were obtained from Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…Hydroxyoctan-7-one 5 was prepared by reduction of hydroxy-3-octen-7-one (1 g, 7 mmol) with hydrogen in the presence of 5% Pd-carbon (1 g) in dry ethyl acetate (30 ml) for 24 h. The 7-azioctanol 6 was synthesized in 39% yield from hydroxyoctan-7-one essentially by the procedure described for the synthesis of 3-azioctanol (13). The UV spectrum in dichloromethane had a max of 348 nm, characteristic of the diazirine group (20).…”

Section: Methodsmentioning

confidence: 99%

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Geometric Isomers of a Photoactivable General Anesthetic Delineate a Binding Site on Adenylate Kinase

Addona¹,

Husain²,

Stehle³

et al. 2002

Journal of Biological Chemistry

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General anesthetics are a class of drugs whose mode of action is poorly understood. Here, two photoactivable general anesthetics, n-octan-1-ol geometric isomers bearing a diazirine group on either the third or seventh carbon (3-and 7-azioctanol, respectively), were used to locate and delineate an anesthetic site on adenylate kinase. Each photoincorporated at a mole ratio of 1:1 as determined by mass spectrometry. The photolabeled kinase was subjected to tryptic digest, and the fragments were separated by chromatography and sequenced by mass spectrometry. 3-Azioctanol photolabeled His-36, whereas its isomer, 7-azioctanol, photolabeled Asp-41. Inspection of the known structure of adenylate kinase shows that the side chains of these residues are within ϳ5 Å of each other. This distance matches the separation of the 3-and 7-positions of an extended aliphatic chain. The alkanol site so-defined spans two domains of adenylate kinase. His-36 is part of the CORE domain, and Asp-41 belongs to the nucleotide monophosphate binding domain. Upon ligand binding the nucleotide monophosphate binding domain rotates relative to the CORE domain, causing a conformational change that might be expected to affect alkanol binding. Indeed, the substrate-mimicking inhibitor adenosine-(5)-pentaphospho-(5)-adenosine (Ap5A) reduced the photoincorporation of 3-[ 3 H]azioctanol by 75%.

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“…3-Azibutan-1-ol was synthesized as previously reported (20). All other reagents were obtained from Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Geometric Isomers of a Photoactivable General Anesthetic Delineate a Binding Site on Adenylate Kinase

Addona¹,

Husain²,

Stehle³

et al. 2002

Journal of Biological Chemistry

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“…Following exposure to UV light, the carbene diradical formed by N2 elimination from the diazirine has an exceedingly short half-life, with diffusion-limited reactivity with water (46). Thus, in the presence of an HDL binding partner such as PON1, UV light exposure is anticipated to produce a covalent adduct only with PON1 residues in close enough spatial proximity to the lipid phase of nHDL to exclude water ( Figure 5A).…”

Section: Pon1 Tyr 71 Is a Functionally Important Site For Hdl Interacmentioning

confidence: 99%

Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

Huang¹,

Wu²,

Riwanto³

et al. 2013

J. Clin. Invest.

240

216

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Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr 71 ), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.

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“…Most P-glycoprotein substrates or inhibitors are weak bases or lipophilic uncharged molecules such as steroid hormones [1,29]. Passive diffusion of the uncharged basic substrate is faster than transport of the protonated form.…”

Section: Implications For the Mechanism Of Action Of The Multidrug Exmentioning

confidence: 99%

ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein

et al. 1994

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The ATP-dependent transport of the three 3H-labeled, amphiphilic cations quinidine, N-(n-pentyl)-quinidinium, and N-(4',4'-azo-n-pentyl)-21-deoxyajmalinium was studied in rat canalicular plasma membrane vesicles. N-Alkylation of quinidine with an n-pentyl residue resulted in a permanently charged cationic substrate for ATP-dependent transport which exhibited a IO-fold higher transport rate relative to quinidine. The K, value was 0.4 PM for N-(n-pentyl)-quinidinium and 5 PM for quinidine. The permanently cationic and photolabile derivative of ajmaline, N-(4',4'-azo-n-pentyl)-21-deoxyajmalinium, was also an efficient substrate and served to label canalicular membrane proteins with molecular masses of 143 kDa and 108 kDa. ATP-dependent transport of the permanently charged amphiphilic cations was inhibited by the P-glycoprotein inhibitors and substrates quinidine, verapamil, and daunorubicin. The data demonstrate that N-alkylation of quinidine and ajmaline results in most efficient substrates for mdrl P-glycoprotein-mediated ATP-dependent transport.

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Diazirines. II. Synthesis and properties of small functionalized diazirine molecules. Observations on the reaction of a diaziridine with the iodine-iodide ion system

Cited by 109 publications

References 0 publications

Geometric Isomers of a Photoactivable General Anesthetic Delineate a Binding Site on Adenylate Kinase

Geometric Isomers of a Photoactivable General Anesthetic Delineate a Binding Site on Adenylate Kinase

Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein

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