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Structure-Activity Relationships and Drug Design01:28

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Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
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Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
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Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
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Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

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Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
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Cholinergic Antagonists: Chemistry and Structure-Activity Relationship01:29

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Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic...
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Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.

Amanda F Ghilardi1, Elham Yaaghubi1, Renan B Ferreira1

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Cyclic thiosulfonate molecules, known as disulfide-bond disrupting agents (DDAs), selectively kill HER-family-overexpressing breast cancer cells. Their anticancer activity is linked to covalent binding with protein disulfide isomerase (PDI) and tunable thiol-reactivity.

Keywords:
AnticancerBreast cancerCyclic thiosulfonateProtein disulfide isomerase inhibitorsThiol reactivityThiosulfonateTunable ring opening

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Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • Epidermal Growth Factor Receptor (EGFR) and Human Epidermal growth factor Receptor 2 (HER2) are key targets in breast cancer therapy.
  • Disulfide bonds play critical roles in protein structure and function, including in cancer cell signaling pathways.
  • Disulfide-bond disrupting agents (DDAs) offer a novel therapeutic strategy by targeting these essential bonds.

Purpose of the Study:

  • To elucidate structure-property-function relationships of cyclic thiosulfonate DDAs.
  • To investigate the mechanism of DDA action involving the protein disulfide isomerase (PDI) family.
  • To optimize DDA compounds for enhanced efficacy against HER-family-overexpressing breast cancer.

Main Methods:

  • Synthesis and structural modification of cyclic thiosulfonate analogs.
  • In vitro assays to assess DDA activity against EGFR+ and HER2+ breast cancer cells.
  • Biochemical studies to determine the covalent binding mechanism with PDI cysteine residues.
  • Structure-activity relationship (SAR) analyses correlating chemical structure with biological potency.

Main Results:

  • Cyclic thiosulfonate DDAs selectively induce apoptosis in EGFR+ or HER2+ breast cancer cells.
  • DDAs covalently bind to the active site cysteine of PDI family members, disrupting disulfide bonds.
  • Structural modifications to the thiosulfonate pharmacophore modulate thiol-reactivity and anticancer activity.
  • Optimization efforts led to compounds with significantly reduced IC50/IC90 values against HER-family-overexpressing breast cancer cells.

Conclusions:

  • Cyclic thiosulfonates represent a promising class of anticancer agents targeting HER-family-driven breast cancers.
  • The mechanism of action involves specific covalent inhibition of PDI, leading to cancer cell apoptosis.
  • Tuning the thiol-reactivity of DDAs through structural modifications is key to enhancing their therapeutic potential.