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

  • ️Sun Jan 01 2017

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. 2017.

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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