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. 2017 Feb 9;60(3):839-885.
doi: 10.1021/acs.jmedchem.6b00788. Epub 2016 Dec 20.

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Paul A Jackson  1 , John C Widen  2 , Daniel A Harki  2 , Kay M Brummond  1
Affiliations

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Paul A Jackson et al. J Med Chem. .

Abstract

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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Figures

Figure 1
Figure 1
HCV protease inhibitors.
Figure 2
Figure 2
Reversible and irreversible EGFR inhibitors.
Figure 3
Figure 3
FGFR and Btk inhibitors.
Figure 4
Figure 4
Pan JNK 1/2/3 inhibitors.
Figure 5
Figure 5
PI3Kα and VEGFR-2 inhibitors.
Figure 6
Figure 6
Inhibitors of Src kinases.
Figure 7
Figure 7
Nek2 inhibitors.
Figure 8
Figure 8
Dual EGFR/VEGFR-2 inhibitor.
Figure 9
Figure 9
Rapidly reversible nitrile-containing Michael acceptors.
Figure 10
Figure 10
Example of a microcystin.
Figure 11
Figure 11
Structure of thalassospiramide A.
Figure 12
Figure 12
Structure of pyrrocidine A.
Figure 13
Figure 13
Natural products containing α-methylene, α-benzylidene, or α-ethylidene lactams.
Figure 14
Figure 14
Inhibitors of human rhinovirus 3C protease (HRV-3CP).
Figure 15
Figure 15
Michael acceptors and pseudo-first order reaction rates with N-acetyl-cysteine methyl ester.
Figure 16
Figure 16
Irreversible papain inhibitors.
Figure 17
Figure 17
Inhibitors of CRM1-mediated nucleocytoplasmic transport and their IC50 values.
Figure 18
Figure 18
Kozusamycin A with analogs and cytotoxicity towards HPAC cells.
Figure 19
Figure 19
Examples of cardenolide natural products containing a butenolide.
Figure 20
Figure 20
Structures of α-methylene-γ-lactone-containing natural products.
Figure 21
Figure 21
Structures of pseudoguaianolides.
Figure 22
Figure 22
Natural product α-methylene-γ-lactones and prodrug derivative (fumarate salt of 201 not shown for clarity).
Figure 23
Figure 23
Structures of arglabin and derivatives.
Figure 24
Figure 24
Reduction in cytotoxicity (IC50) when substituents are on the exocyclic methylene.
Figure 25
Figure 25
Melampomagnolide B and biotinylated derivative used for pulldown studies.
Figure 26
Figure 26
Library of α-methylene-γ-lactones containing terminal alkynes used as biological probes for the discovery of novel anti-microbial targets.
Figure 27
Figure 27
Styryl dienones and proposed mechanism for ortho-hydroxy substituent effect.
Figure 28
Figure 28
Styryl ketones and similar Mannich bases.
Figure 29
Figure 29
Structure of curcumin.
Figure 30
Figure 30
Resorcylic acid lactones with IC50 values for inhibition of TNFα-PLAP.
Figure 31
Figure 31
Synthetic resorcylic acid lactone analogs.
Figure 32
Figure 32
Selected CyPGs structures.
Figure 33
Figure 33
Proposed structure of CyPG crosslinking H-Ras C-terminal peptide (K170-K185).
Figure 34
Figure 34
Natural product (351-354) and synthetic (355-357) cyclopentenediones with biological activity.
Figure 35
Figure 35
α-Nitrile cyclohexenone dually activated Michael acceptors.
Figure 36
Figure 36
Illudin natural products and synthetic derivatives.
Figure 37
Figure 37
Examples of Bioactive α-haloacrolyl compounds.
Figure 38
Figure 38
Examples of biologically active rhodanines.
Figure 39
Figure 39
Rhodanines and analogs that did not form detectable adducts with GSH.
Figure 40
Figure 40
Compounds reactive toward cysteamine.
Figure 41
Figure 41
Compounds nonreactive toward cysteamine.
Figure 42
Figure 42
Classification of scaffolds by 13C NMR chemical shift values.
Figure 43
Figure 43
Relative experimental rates of GSH addition to α,β-unsaturated carbonyls.
Scheme 1
Scheme 1
Dimethyl Fumarate Hydrolysis
Scheme 2
Scheme 2
Relative Rates of GSH Addition to N-Arylacrylamides
Scheme 3
Scheme 3
Rakicidin A and Analog that Forms a 1,6-Addition Product with Methyl Thioglycolate
Scheme 4
Scheme 4
Thiol Addition to Pyrrolinones
Scheme 5
Scheme 5
Thiol Adduct Formation with α-Methylene-γ-lactams and Oxindoles
Scheme 6
Scheme 6
Thiol Addition to Unsaturated Sugars
Scheme 7
Scheme 7
Thiol Addition to α,β-Unsaturated-δ-valerolactones
Scheme 8
Scheme 8
Thiol Addition to Dually Activated Chromones
Scheme 9
Scheme 9
Thiol Addition Reactions to Coumarins
Scheme 10
Scheme 10
Effect of Alkyl Substitution on Thiol Addition to Butenolides
Scheme 11
Scheme 11
Thiol Adducts as Double Bond Protecting Groups
Scheme 12
Scheme 12
Thiol Addition to γ-Methylene or γ-Alkylidene Butenolides
Scheme 13
Scheme 13
Generic Chalcone and Addition of Cysteamine to 2' Hydroxy Chalcone
Scheme 14
Scheme 14
Reversibility of Glutathione Adducts of Curcumin Analogs
Scheme 15
Scheme 15
Equilibrium Formation of Thiol Adducts of PGA1 and Δ7-PGA1 Methyl Esters
Scheme 16
Scheme 16
Formation of Thiol Adducts with Clavulone Derivatives
Scheme 17
Scheme 17
Reactions and Reversibility of Clavulone Derivatives with Thiols
Scheme 18
Scheme 18
Nucleophilic Addition to Exocyclic vs Endocyclic Enones of Cyclopentenones
Scheme 19
Scheme 19
Equilibrium Formation of Thiol Adducts with Cyclopentenones
Scheme 20
Scheme 20
Cysteine and Propanethiol Addition to a Triquinane
Scheme 21
Scheme 21
Selected Kaurane Natural Products and the Reaction of Oridonin with Thiols
Scheme 22
Scheme 22
Addition of Cysteamine to a Cryptocaryone Analog
Scheme 23
Scheme 23
Mechanism of Thiol Activation of Calicheamicin and Thiol Addition to a Derivative
Scheme 24
Scheme 24
Synthesis of Sulfenic Acid Probe and Thiol Reactivity of Cyclopentenediones
Scheme 25
Scheme 25
Reactions of Aldehydes with Thiols
Scheme 26
Scheme 26
Dually Activated Michael Acceptors
Scheme 27
Scheme 27
Reversibility of Dually Activated Michael Acceptors and RSK2 Inhibitors
Scheme 28
Scheme 28
Tunable Reversibility of α-Heteroaromatic-Substituted Acrylonitriles
Scheme 29
Scheme 29
Effect of β-Substituent on the Reversibility of Thiol Addition to Dually Activated Michael Acceptors
Scheme 30
Scheme 30
Mechanism for Direct Thiol Alkylation of Hydroxymethylacylfulvene
Scheme 31
Scheme 31
Products Obtained from the Reaction of HMAF with Thiols
Scheme 32
Scheme 32
Reactions of α-Bromocyclopentenone with Thiols and DNA
Scheme 33
Scheme 33
Products of Thiol Addition to α-Halo Butenolide with Proposed Intermediate
Scheme 34
Scheme 34
Reversible Additions of Thiols to Rhodanines and Related Scaffolds
Scheme 35
Scheme 35
Reaction of Thiol and Amine Nucleophiles with Wortmannin
Scheme 36
Scheme 36
Crossover Experiments Showing the Reversibility of Wortmannin Adducts
Scheme 37
Scheme 37
Reaction of Monomethyl Fumarate with GSH
Scheme 38
Scheme 38
Reaction of Fumaric Acid with GSH
Scheme 39
Scheme 39
pH Dependence of Thiol Reactive Quinolines
Scheme 40
Scheme 40
Coumarin Based Fluorogenic Probes and Second Order Rates Constants for GSH Addition
Scheme 41
Scheme 41
Fluorescence of Quinazoline Michael Acceptors upon Covalent Modification of a Cysteine in c-Src
Scheme 42
Scheme 42
Reaction of α,β-Unsaturated Aldehydes with Cysteamine
Scheme 43
Scheme 43
Methyl Cinnamates in Order of Decreasing Rates of GSH Addition
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