Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?
Abstract
:1. Introduction
- Phosphorylation regulates numerous cellular processes such as the cell cycle, and growth and signal transduction pathways [2].
- Acetylation primarily affects protein stability and interactions and often occurs at the N-terminus [3].
- Ubiquitination signals protein degradation [4].
- Methylation alters the interactions of proteins with DNA, RNA or other proteins [5].
- Glycosylation affects the folding, stability and cell adhesion of proteins [6].
- Oxidation occurs when reactive oxygen species (ROS) donate electrons to proteins. It can extensively modify the primary structure of proteins and peptides and often leads to modifications of higher-order structures. It is implicated in human disease, carcinogenesis and aging [7].
2. Michael Reaction and Covalent Binding to Proteins
2.1. Michael Reaction
2.2. The Kinetics of Inhibition via Michael Reaction
2.3. Reversible and Irreversible Covalent Binding to Proteins
- Drug discovery and development, by covalently binding to specific target proteins, thereby inhibiting their function or altering their activity.
- Inhibition of enzymes by binding to and inactivating them, thereby interfering with the regulation of cellular processes.
- Protein engineering, inducing covalent modifications in proteins modifies their stability, function or other properties.
3. Transcription Factors That May Be Potential Targets of Michael Acceptor Compounds in Neoplastic Metabolism
- They can interact with transcription factors, altering their ability to activate or repress the transcription of certain genes [49].
- They can affect the stability of mRNA and thus influence the production of certain proteins. Changes in mRNA stability have a significant impact on protein production in cells [50].
3.1. Transcription Factor NF-κB
3.2. Transcription Factor PPAR-γ
- PPAR-γ agonists can suppress inflammatory responses in psoriatic skin lesions and attenuate associated comorbidities [63].
- Neurodegenerative diseases, signaling networks, insulin sensitivity, glucose homeostasis, fatty acid oxidation, immune responses, redox balance, cardiovascular integrity and cell fate depend on the PPAR-γ factor [64]. PPAR-γ agonists can reduce amyloid and tau pathologies, and neuroinflammation and improve memory impairment in models of Alzheimer’s disease [65].
- Suppression of PPAR-γ under disease conditions exacerbates inflammatory and fibrogenic factors, contributing to kidney damage [66].
- PPAR-γ is associated with susceptibility to neuronal damage in models of brain disease [67].
3.3. Transcription Factor STAT3
- STAT3 contributes to metastasis and drug resistance; its hyperactivation is associated with a poor clinical prognosis in most human cancers [74].
- STAT3 is observed in both cancer and non-cancer cells in the tumor microenvironment, inhibits the expression of immune activation and promotes immunosuppressive factors, thus contributing to tumor progression [75].
- The interplay between STAT3 and non-coding RNAs has attracted attention and highlighted its regulatory role in gene expression networks [76].
3.4. The Nuclear Export Receptor Exportin-1
3.5. Oncoprotein c-Myc
4. Michael Acceptors in Current Chemotherapy Treatments
4.1. Tyrosine Kinase Inhibitors (TKIs)
4.2. Cyclin-Dependent Kinases (CDKs) Inhibitors
4.3. Aurora Kinase (AURK) Inhibitors
4.4. Bruton’s Tyrosine Kinase (BTK) Inhibitors
4.5. Nitro Fatty Acids (NO2-FAs)
4.6. Anthracycline Family of Chemotherapy Drugs
- Doxorubicin, which is used in the treatment of breast cancer, lung cancer, ovarian cancer, liver cancer, thyroid cancer, leukemias and lymphomas [135].
- Daunorubicin, which is used in the treatment of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and Kaposi’s sarcoma.
- Epirubicin, which is used for breast cancer, ovarian cancer, stomach cancer, lung cancer and lymphoma.
- Idarubicin, which is prescribed for acute myeloid leukemia.
4.7. Family of Selective Inhibitors of Nuclear Export (SINEs)
5. Natural Michael Acceptors in Cancer Prevention and Treatment
5.1. Alkaloids
5.2. Terpenes and Terpenoids
5.2.1. Sesquiterpenes
5.2.2. Diterpenoids
5.2.3. Triterpenoids or Steroids
5.2.4. Tetraterpenoids
5.2.5. Hop-Derived Bitter Acids
5.3. Polyketides
- They show anti-cancer activity against various types of cancer, including breast, lung, colon and prostate cancer [217].
- They have anti-inflammatory properties that could be useful in the treatment of inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease [218].
- They have antiparasitic activity against parasites, including the parasite that causes malaria [223].
5.4. Polyphenols
5.4.1. Esters Derived from Caffeic Acid
- Caffeic acid phenethyl ester (CAPE), a phenolic compound recognized as one of the major active components in propolis, with significant biological activities [237].
- Dactylifric acid (DA), also known as date acid or 5-O-caffeoylshikimic acid, an ester derived from caffeic acid and shikimic acid, found mainly in dates (Phoenix dactylifera fruits) [238].
- Chlorogenic acid (CGA), the ester formed from caffeic acid and quinic acid. The collective term “chlorogenic acids” refers to a family of related polyphenols that include hydroxycinnamic acids bound to quinic acid (such as caffeic acid, ferulic acid and p-coumaric acid). Chlorogenic acids are widely used in foods such as coffee beans, coffee drinks, mate and tea and include numerous isomers, each with different sensory properties [239].
- Rosmarinic acid (RA), isolated from Rosmarinus officinalis L., and commonly known as rosemary.
5.4.2. Chalcones
5.4.3. Curcuminoids
- Protecting cells from free radical damage that contributes to aging and disease [268].
- They show neuroprotective effects by protecting brain cells from oxidative stress and inflammation, both of which are associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s [269].
- They have anti-inflammatory properties that are crucial in combating chronic inflammation such as arthritis, cancer and cardiovascular disease [270].
- They have shown anti-tumor properties in laboratory studies, which has led to ongoing clinical trials to investigate their effectiveness in cancer treatment [271].
- They have an anti-acidifying effect, which may be beneficial for people with heartburn or acid reflux as it reduces gastric acid secretion.
- They act as a radioprotective agent by protecting cells from radiation-induced damage, which is particularly beneficial for people undergoing radiotherapy for cancer [272].
- They relieve arthritis symptoms by reducing inflammation and associated pain [273].
5.4.4. Flavonoids
5.4.5. Coumarins
- Difficulty in large-scale isolation: they are often difficult to isolate in large quantities, which can hinder their development into drugs.
- Understanding the action mechanism can be challenging, which can slow down their pharmaceutical development.
- Pharmaceutical development challenges: even when they show promising anti-cancer properties, it can be difficult to develop them into a drug that can be used in clinical settings.
- Bioavailability and solubility issues of MA, such as curcumin or resveratrol, have shown potent anti-cancer activity but have poor solubility and bioavailability when administered alone.
6. Antibody and Peptide-Mediated Delivery of Michael Acceptors
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Andrés, C.M.C.; Pérez de la Lastra, J.M.; Bustamante Munguira, E.; Andrés Juan, C.; Pérez-Lebeña, E. Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality? Int. J. Mol. Sci. 2024, 25, 6099. https://doi.org/10.3390/ijms25116099
Andrés CMC, Pérez de la Lastra JM, Bustamante Munguira E, Andrés Juan C, Pérez-Lebeña E. Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality? International Journal of Molecular Sciences. 2024; 25(11):6099. https://doi.org/10.3390/ijms25116099
Chicago/Turabian StyleAndrés, Celia María Curieses, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan, and Eduardo Pérez-Lebeña. 2024. "Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?" International Journal of Molecular Sciences 25, no. 11: 6099. https://doi.org/10.3390/ijms25116099
APA StyleAndrés, C. M. C., Pérez de la Lastra, J. M., Bustamante Munguira, E., Andrés Juan, C., & Pérez-Lebeña, E. (2024). Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality? International Journal of Molecular Sciences, 25(11), 6099. https://doi.org/10.3390/ijms25116099