Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

Lee, Kwan Hee; McPhee, Fiona; DeVoss, James J.; Craik, Charles S.; Montellano, Paul R. Ortiz de

doi:10.1021/jo00100a021

Cited by 5 publications

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“…We have shown in earlier work that a wide range of haloperidol derivatives inhibit both HIV-1 PR and HIV-2 PR. 22,25 Two crystal structures have been reported which show that a single haloperidol derivative can bind in two very different orientations within the active site of the protein. 26 The other three epoxides were incorporated into frameworks based on a new class of FMOC derivatives identified as reversible inhibitors of the HIV proteases (unpublished results).…”

Section: Resultsmentioning

confidence: 99%

“…K 2CO3 (386 mg, 2.7 mmol) and 4-(p-chlorophenyl)-4hydroxypiperidine (485 mg, 2.3 mmol) were added to a solution of the crude 1-phenyl-1,2-epoxy-3-bromopropane (700 mg, 12.3 mmol) in DMF, and the mixture was refluxed for 1.5 h. The suspension was then filtered, and the precipitate was washed with ethyl acetate. Evaporation of the solvent from the filtrate followed by flash chromatography on silica gel with ethyl acetate as the eluant provided 128 mg of purified material (16% yield): IR (neat) 3383 (br), 2950, 2821, 1678, 1635, 1604, 1493, 1462, 1370, 1098, 1048, 1011, 906, and 820 cm -1 ; 1 (20), 212 (25); HRMS for C20H22ClNO2, calcd 343.1339, found 343.1337.…”

Section: Methodsmentioning

confidence: 99%

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Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Caldera

McPhee

et al. 1996

J. Am. Chem. Soc.

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Irreversible inhibition of the HIV-1 protease by agents that specifically alkylate its catalytic aspartate residues is a potentially useful approach for circumventing the evolution of HIV strains that are resistant to protease inhibitors. Five haloperidol- and two FMOC-based epoxides of differing reactivities have been synthesized and tested as irreversible inhibitors of the HIV-1 protease (HIV-1 PR). Of these, two trisubstituted epoxides, a cis-1,2-disubstituted epoxide, a 1,1-disubstituted epoxide, and a monosubstituted epoxide function as irreversible inhibitors, but two trans-1,2-disubstituted epoxides do not. The most effective of the epoxides (6) inactivates HIV-1 PR with K inact = 65 μM and V inact = 0.009 min-1. 1,2-Epoxy-3-(p-nitrophenoxy)propane (EPNP), a nonspecific inactivating agent for aspartyl proteases, has been used to validate a protocol for establishing the stoichiometry and site of protein alkylation. Mass spectrometric analysis of the inactivated enzyme shows that one molecule of either EPNP or the cyclic 1,2-disubstituted epoxide 6 is covalently bound per HIV-1 PR dimer. Mass spectrometric sequencing of labeled proteolytic peptides shows that both inhibitors are covalently bound to a catalytic aspartate residue. The covalent binding of three α,β-unsaturated ketone derivatives of haloperidol has been similarly examined. Analysis of HIV-1 PR inactivated by these agents establishes that they bind covalently to the two cysteines and the N-terminal amino group but not detectably to the catalytic aspartate residues. The results indicate that aspartate-targeted inactivation of HIV-1 PR depends on (a) matching the reactivity of the alkylating functionality to that of the aspartates, preferably by exploiting the two-aspartate catalytic motif of the protease to activate the alkylating agent, and (b) appropriate positioning of the alkylating functionality within the active site. These requirements are readily met by a monosubstituted, 1,1-disubstituted, or cyclic cis-1,2-disubstituted epoxide but not by trans-1,2-disubstituted epoxides or α,β-unsaturated ketones.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Caldera

McPhee

et al. 1996

J. Am. Chem. Soc.

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“…In a program to prepare inhibitors of B-Raf kinase as cancer therapeutics, it was found that the S N Ar reaction (eq ), under typical conditions, of 2,4-difluoroacetophenone ( 1 ) with (1 S ,4 S )- tert -butyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate ( 2 ) gave a mixture of regioisomers only slightly favoring the desired para -isomer 3a despite the steric hindrance for the ortho -isomer 3b . As the separation of these isomers was nontrivial on the targeted scale, we began a systematic effort to optimize the regioselectivity of this reaction.…”

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Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of S_NAr Reactions of Electron-Deficient Polyfluoroarenes

et al. 2009

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It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.

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Synthesis of Anilines

Hartwig¹,

Shekhar²,

Shen³

et al. 2009

Patai's Chemistry of Functional Groups

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Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

Cited by 5 publications

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Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of S_NAr Reactions of Electron-Deficient Polyfluoroarenes

Synthesis of Anilines

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Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

Cited by 5 publications

References 0 publications

Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Irreversible Inhibition of the HIV-1 Protease: Targeting Alkylating Agents to the Catalytic Aspartate Groups

Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of SNAr Reactions of Electron-Deficient Polyfluoroarenes

Synthesis of Anilines

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Product

Resources

About

Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of S_NAr Reactions of Electron-Deficient Polyfluoroarenes