Moving Past Quinone-Methides: Recent Advances toward Minimizing Electrophilic Byproducts from COS/H2S Donors

2021 ◽  
Vol 21 ◽  
Author(s):  
Michael Pluth
Keyword(s):  
Hydrogen Sulfide ◽  
Carbonic Anhydrase ◽  
Therapeutic Potential ◽  
Carbonyl Sulfide ◽  
Quinone Methide ◽  
Quinone Methides ◽  
On Demand ◽  
Physiological Processes ◽  
Recent Approach ◽  
Alternative Approaches

: Hydrogen sulfide (H2S) is an important biomolecule that plays key signaling and protective roles in different physiological processes. With the goals of advancing both the available research tools and the associated therapeutic potential of H2S, researchers have developed different methods to deliver H2S on-demand in different biological contexts. A recent approach to develop such donors has been to design compounds that release carbonyl sulfide (COS), which is quickly converted to H2S in biological systems by the ubiquitous enzyme carbonic anhydrase (CA). Although highly diversifiable, many approaches using this general platform release quinone methides or related electrophiles after donor activation. Many such electrophiles are likely scavenged by water, but recent efforts have also expanded alternative approaches that minimize the formation of electrophilic byproducts generated after COS release. This mini-review focuses specifically on recent examples of COS-based H2S donors that do not generate quinone methide byproducts after donor activation.

Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

2019 ◽  
Author(s):  
Matthew M. Cerda ◽  
Jenna L. Mancuso ◽  
Emma J. Mullen ◽  
Christopher H. Hendon ◽  
Michael Pluth
Keyword(s):  
Hydrogen Sulfide ◽  
Carbonic Anhydrase ◽  
Carbonyl Sulfide ◽  
Intermediate Formation ◽  
Activation Energies ◽  
Quinone Methide ◽  
Enzymatic Conversion ◽  
Sulfur Species ◽  
Alkyl Substitution ◽  
The Impact

<p>The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H<sub>2</sub>S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H<sub>2</sub>S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H<sub>2</sub>S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the intermediate formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H<sub>2</sub>S donor motifs and that these groups release two equivalents of COS/H<sub>2</sub>S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H<sub>2</sub>S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.</p>

Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

2019 ◽  
Author(s):  
Matthew M. Cerda ◽  
Jenna L. Mancuso ◽  
Emma J. Mullen ◽  
Christopher H. Hendon ◽  
Michael Pluth
Keyword(s):  
Hydrogen Sulfide ◽  
Carbonic Anhydrase ◽  
Carbonyl Sulfide ◽  
Intermediate Formation ◽  
Activation Energies ◽  
Quinone Methide ◽  
Enzymatic Conversion ◽  
Sulfur Species ◽  
Alkyl Substitution ◽  
The Impact

<p>The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H<sub>2</sub>S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H<sub>2</sub>S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H<sub>2</sub>S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the intermediate formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H<sub>2</sub>S donor motifs and that these groups release two equivalents of COS/H<sub>2</sub>S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H<sub>2</sub>S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.</p>

Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

2019 ◽  
Vol 25 (26) ◽  
pp. 2892-2905 ◽  
Author(s):  
Sumit Jamwal ◽  
Ashish Mittal ◽  
Puneet Kumar ◽  
Dana M. Alhayani ◽  
Amal Al-Aboudi
Keyword(s):  
Nervous System ◽  
Therapeutic Potential ◽  
The Body ◽  
Membrane Receptors ◽  
Physiological Importance ◽  
Physiological Processes ◽  
Central Nervous Systems ◽  
Energy Consuming ◽  
Metabolic Dysfunctions ◽  
G Protein Coupled

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

scholarly journals Alternative approaches to target Myc for cancer treatment

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Chen Wang ◽  
Jiawei Zhang ◽  
Jie Yin ◽  
Yichao Gan ◽  
Senlin Xu ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Small Molecules ◽  
Drug Target ◽  
The Past ◽  
Physiological Processes ◽  
Alternative Approaches ◽  
Global Transcriptome ◽  
Factor C ◽  
Signaling Modules ◽  
Druggable Targets

AbstractThe Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its “undruggable” properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

A solid thermal and fast synthesis of MgAl-hydrotalcite nanosheets and their applications in the catalytic elimination of carbonyl sulfide and hydrogen sulfide

2021 ◽  
Vol 45 (7) ◽  
pp. 3535-3545
Author(s):  
Guanqing Zhang ◽  
Xun Kan ◽  
Yong Zheng ◽  
Yanning Cao ◽  
Shijiang Liang ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Carbonyl Sulfide ◽  
Superior Performance ◽  
Fast Synthesis

MgAl hydrotalcites with high exposed OH− sites were designed, and showed superior performance for the catalytic elimination of COS and H2S.

Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential

2010 ◽  
Vol 120 (6) ◽  
pp. 219-229 ◽  
Author(s):  
Madhav Lavu ◽  
Shashi Bhushan ◽  
David J. Lefer
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Hydrogen Sulfide ◽  
Therapeutic Potential ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Signalling Molecule ◽  
Anti Inflammatory ◽  
Antioxidant Effects

H2S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and metabolism of H2S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.

scholarly journals Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

2015 ◽  
Vol 172 (6) ◽  
pp. 1479-1493 ◽  
Author(s):  
Eelke M Bos ◽  
Harry van Goor ◽  
Jaap A Joles ◽  
Matthew Whiteman ◽  
Henri G D Leuvenink
Keyword(s):  
Hydrogen Sulfide ◽  
Therapeutic Potential ◽  
Physiological Properties

A new dehydrogenative [4 + 1] annulation between para-quinone methides (p-QMs) and iodonium ylides for the synthesis of 2,3-dihydrobenzofurans

2018 ◽  
Vol 5 (23) ◽  
pp. 3483-3487 ◽  
Author(s):  
Yan-Jie Xiong ◽  
Shao-Qing Shi ◽  
Wen-Juan Hao ◽  
Shu-Jiang Tu ◽  
Bo Jiang
Keyword(s):  
Quinone Methide ◽  
Quinone Methides ◽  
Iodonium Ylides

A new dehydrogenative [4 + 1] annulation of para-quinone methides (p-QMs) with acyclic and cyclic iodonium ylides has been established, delivering a variety of functionalized 2,3-dihydrobenzofurans with the retention of the quinone methide unit in generally good yields.

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