Research progress of indole-fused derivatives as allosteric modulators: Opportunities for drug development

Luo, Meng-Lan; Zhao, Qian; He, Xiang‐Hong; Xie, Xin; Zhu, Hongping; You, Feng-Ming; Peng, Cheng; Zhan, Gu; Huang, Wei

doi:10.1016/j.biopha.2023.114574

Cited by 6 publications

(6 citation statements)

References 80 publications

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“…Therefore, BI has been used as a scaffold for several semisynthetic derivatives that exhibit promise as enhanced pharmaceutical agents [ 36 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. The indole scaffold has significant importance within the domains of medical chemistry and organic chemistry [ 61 , 62 , 63 , 64 ]. According to reports, indole derivatives have been shown to have allosteric characteristics in relation to a range of G protein-coupled receptors (GPCRs).…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that these chemicals have the ability to interact with GPCRs and elicit alterations in their structure or conformational transitions, thereby impacting their signal transduction and overall functionality [ 65 , 66 ]. The aforementioned findings have significant implications for the advancement of GPCR modulators and their potential therapeutic applications in the management of many ailments, including neurological diseases and cancer [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation

Lombrea,

Watz,

Bora

et al. 2023

Plants

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The prevalence and severity of skin cancer, specifically malignant melanoma, among Caucasians remains a significant concern. Natural compounds from plants have long been explored as potential anticancer agents. Betulinic acid (BI) has shown promise in its therapeutic properties, including its anticancer effects. However, its limited bioavailability has hindered its medicinal applications. To address this issue, two recently synthesized semisynthetic derivatives, N-(2,3-indolo-betulinoyl)diglycylglycine (BA1) and N-(2,3-indolo-betulinoyl)glycylglycine (BA2), were compared with previously reported compounds N-(2,3-indolo-betulinoyl)glycine (BA3), 2,3-indolo-betulinic acid (BA4), and BI. These compounds were evaluated for their effects on murine melanoma cells (B164A5) using various in vitro assays. The introduction of an indole framework at the C2 position of BI resulted in an increased cytotoxicity. Furthermore, the cytotoxicity of compound BA4 was enhanced by conjugating its carboxylic group with an amino acid residue. BA2 and BA3, with glycine and glycylglycine residues at C28, exhibited approximately 2.20-fold higher inhibitory activity compared to BA4. The safety assessment of the compounds on human keratinocytes (HaCaT) has revealed that concentrations up to 10 µM slightly reduced cell viability, while concentrations of 75 µM resulted in lower cell viability rates. LDH leakage assays confirmed cell membrane damage in B164A5 cells when exposed to the tested compounds. BA2 and BA3 exhibited the highest LDH release, indicating their strong cytotoxicity. The NR assay revealed dose-dependent lysosome disruption for BI and 2,3-indolo-betulinic acid derivatives, with BA1, BA2, and BA3 showing the most cytotoxic effects. Scratch assays demonstrated concentration-dependent inhibition of cell migration, with BA2 and BA3 being the most effective. Hoechst 3342 staining revealed that BA2 induced apoptosis, while BA3 induced necrosis at lower concentrations, confirming their anti-melanoma properties. In conclusion, the semisynthetic derivatives of BI, particularly BA2 and BA3, show promise as potential candidates for further research in developing effective anti-cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation

Lombrea,

Watz,

Bora

et al. 2023

Plants

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Section: Allosteric Modulatorsmentioning

confidence: 99%

“…Allosteric modulators can change the protein/substrate affinity in a highly predictable manner by stabilizing target proteins in an inactive or active state, leading to desirable controllability. [236][237][238][239][240][241] Allosteric modulators offer several advantages over orthosteric inhibitors. Firstly, allosteric ligands do not have to compete with high-affinity substrates, making it simpler to develop allosteric modulators.…”

Section: Allosteric Modulatorsmentioning

confidence: 99%

“…These findings highlight the enormous therapeutic potential that can be further enhanced in combination with other chemotherapeutic agents or radiotherapy. 574 In 2006, Kabilova and colleagues synthesized siRNAs, compound (241), targeting different specific regions of the c-Myc mRNA using both enzymatic and chemical methods. Both types of synthesized siRNAs were effective in reducing c-Myc mRNA levels in KB-3-1 human epidermoid carcinoma cells, leading to inhibition of cell proliferation.…”

Section: Lysosome-based Tpdmentioning

confidence: 99%

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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Xie,

Yu,

et al. 2023

Sig Transduct Target Ther

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Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting “undruggable” proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.

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Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation

Hashimoto,

Taguchi,

Kasagi

et al. 2024

J. Org. Chem.

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Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.

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Research progress of indole-fused derivatives as allosteric modulators: Opportunities for drug development

Cited by 6 publications

References 80 publications

Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation

Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation

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