Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier

Sharma, Ram; Chatterjee, Esha; Mathew, Jacob; Sharma, Sachin; Rao, N. Vijayakameswara; Pan, Chun Hsu; Lee, Sung Bau; Dhingra, Ashwani Kumar; Grewal, Ajmer Singh; Liou, Jing Ping; Guru, Santosh Kumar; Nepali, Kunal

doi:10.1016/j.ejmech.2022.114602

Cited by 9 publications

(3 citation statements)

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“…Moreover, genetic/epigenetic alterations could affect PD-L1 expression as well. For example, in squamous cell NSCLC elevated levels of histone deacetylases (HDAC), such as HDAC3 and HDAC6, are detected, that are reported to upregulate PD-L1 expression by STAT3 signalling pathway in melanoma, osteosarcoma, and pancreatic cancer [ 77 , 78 ]. Furthermore, PD-L1 expression in dendritic cells in the TME and PD-L1 transcription in tumour cells are elevated through increased interferon -γ (IFN-γ) production and acetylation of PD-L1 promoter region histone after HDAC3 expression inhibition [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

Gurevičienė,

Matulionė,

Poškienė

et al. 2024

Medicina

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Background and Objectives: Although perioperative immunotherapy is implemented as a standard of care for resected non-small cell lung cancer (NSCLC), there is unmet need for predictive biomarkers as programmed death-ligand 1 (PD-L1) is not the perfect one. The functionality of tumour-infiltrating immune cells in the tumour microenvironment (TME) and the involvement in immune system response is one of the crucial factors that lead to pro- or anti-tumourigenic role and could predict response to PD-1 and PD-L1 inhibitors. So, the investigation of PD-L1 expression in the context of TME in early stages of resected NSCLC is urgent required. Materials and Methods: PD-L1 expression by three scoring methods: tumour proportion score (TPS), immune cell score (IC), and combined proportion score (CPS) was assessed in 72 archival tumour tissue specimens from stage I–III surgically resected NSCLC patients and associations with immune cells in TME were explored. Results: PD-L1 expression ≥1% evaluated by TPS, IC, and CPS was detected in 28%, 36%, and 39% of cases and moderate, substantial, and strong agreement between TPS and IC, TPS and CPS, CPS and IC was detected (Cohen’s κ coefficient 0.556, 0.63, and 0.941, respectively). PD-L1 TPS, IC, and CPS correlated with smoking intensity defined as pack-years (r = 0.0305, p = 0.012; r = 0.305, p = 0.013, and r = 0.378, p = 0.002, respectively). Only PD-L1 TPS was associated with squamous cell carcinoma (p = 0.028). PD-L1 IC ≥1% was more often seen in tumours with high CD4+ T cells infiltration (p = 0.02), while PD-L1 CPS ≥1%—in tumours with high CD4+ and CD8+ T cells infiltration (p = 0.021 and p = 0.048, respectively). PD-L1 IC and CPS ≥10% was more often detected in tumours with greater number of tumour-infiltrating CD4+Foxp3+ T cells (p = 0.01 and p = 0.025, respectively). PD-L1 TPS ≥50% was associated with higher probability to detect greater number of tumour-infiltrating M2 macrophages (p = 0.021). No association was found between PD-L1 alone or in combination with tumour-infiltrating lymphocytes, macrophages, and disease-free or overall survival. Conclusions: This study results revealed that rates of PD-L1 expression correlated among three scoring methods (TPS, IC, and CPS). Moreover, PD-L1 expression was significantly associated with smoking intensity, squamous histology, and tumour-infiltrating immune cells.

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Section: Discussionmentioning

confidence: 99%

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

Gurevičienė,

Matulionė,

Poškienė

et al. 2024

Medicina

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“…1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.24 (s, 1H), 4.60 (t, J = 6.2 Hz, 2H), 3.14 (t, J = 6.8 Hz, 2H), 2.10 (p, J = 6.2 Hz, 2H), 1.99 (p, J = 6.6 Hz, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 180. 24 General procedure for of compounds 13a-13aa.…”

Section: Chemistry Materials and Methodsmentioning

confidence: 99%

“…Naturally-occurring alkaloids deoxyvasicinone [21,22] and mackinazolinone [23] are isolated from the plants Adhatoda vasica and Mackilaya subulata Philipson, respectively. These pyrimidine-based derivatives have demonstrated potential biological properties [24][25][26]. The tricyclic deoxyvasicinone system is part of other biologically important alkaloids including isaindigotone [27], tryptanthrin [28], and luotonin A [29], while mackinazolinone is part of rutaecarpine [30] and evodiamine [31], respectively (Fig.…”

Section: Introductionmentioning

confidence: 99%

Parallel synthesis of condensed pyrimidine-thiones and their antitumor activities

et al. 2022

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Herein we studied the formation of thiones via C=O group conversion into the C=S functional groupbased tricyclic pyrimidinone systems using Lawesson's reagent and phosphorus pentasul de as thionation agents. Naturally-occurring alkaloids deoxyvasicinone and mackinazolinone were selected as templates for the modi cation of furo [2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone scaffold.Research work was performed under the combinatorial and parallel synthesis of pyrimidine-based small molecules, along with a one-pot reaction strategy. All synthesized 54 novel pyrimidine-thiones were elucidated by 1 H-NMR, 13 C-NMR, and HRMS analysis. In addition, both series of thiones were evaluated for their antitumor activity against three types of the human cancer cell: cervical HeLa, breast MCF-7, and colon HT-29 lines. Compound with azepine fragment 13aa (1-methyl-2-(4- 6,7,8,9,10-hexahydro-4H-pyrrolo[2',3':4,5]pyrimido[1,2-a]azepine-4-thione) was most active derivative (IC 50 =2.09±0.22 µM) against the HT-29 cell line.

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Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview

Jaouen,

Bailly

2025

Bioorganic & Medicinal Chemistry

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Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier

Cited by 9 publications

References 54 publications

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

Parallel synthesis of condensed pyrimidine-thiones and their antitumor activities

Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview

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