Design, synthesis, cytotoxic evaluation and molecular docking of novel 1, 3, 4-thiadiazole sulfonamides with azene and coumarin moieties as carbonic anhydrase inhibitors DOI Creative Commons
Samir Bondock,

Tallah Albarqi,

Tamer Nasr

et al.

Arabian Journal of Chemistry, Journal Year: 2023, Volume and Issue: 16(8), P. 104956 - 104956

Published: May 3, 2023

New thiadiazole sulfonamide derivatives were designed as human carbonic anhydrase inhibitors (hCAIs) to develop robust and novel anticancer agents. Tail modification approach was considered in designing the target compounds which synthesized following two-step procedure starting from 5-acetyl-3-N-(4-sulfamoylphenyl)-2-imino-1,3,4-thiadiazoline. Cytotoxic evaluation revealed potent diazene derivative 2 with IC50 1.18 μM, 5.28 μM 7.15 against MCF-7, Caco2 HepG-2, respectively. Moreover, dihydroxyphenyl triazene 5 demonstrated 3.03 5.66 12.50 Caco2, HepG-2 Similarly, carbohydrazide coumarin 18 showed of 2.00 12.30 HepG2, Molecular docking using hCAIX hCAXII adopted explain achieved cytotoxicity on molecular level their silico ADME evaluation.

Language: Английский

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside DOI Open Access
Paul C. McDonald, Shawn C. Chafe, Claudiu T. Supuran

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(14), P. 3297 - 3297

Published: July 6, 2022

Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- extracellular pH acidosis. Significant advances have been made recently in the development therapeutic targeting CAIX. These approaches include antibody-based immunotherapy, as well use antibodies to deliver toxic radioactive payloads. In addition, large number small molecule inhibitors which inhibit enzymatic activity CAIX described. this commentary, we highlight current status strategies both pre-clinical clinical space, discuss future perspectives that leverage inhibition combination with additional targeted therapies enable effective, durable for cancer therapy.

Language: Английский

Citations

76
Carbonic anhydrase IX: An atypical target for innovative therapies in cancer DOI Creative Commons
Roberto Ronca, Claudiu T. Supuran

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189120 - 189120

Published: May 25, 2024

Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX a tumor-associated isoform induced by hypoxia and involved the adaptation of tumor cells to acidosis. Indeed, tumor-driving pathways can induce expression, this turn has been associated cancer invasion metastatic features as well induction stem-like features, drug resistance recurrence. After its functional structural characterization targeting approaches have developed inhibit activity neoplastic tissues, date field seen an incredible acceleration terms therapeutic options biological readouts. Small molecules inhibitors, hybrid/dual drugs, antibodies adoptive (CAR-T based) cell therapy at preclinical level, whereas sulfonamide inhibitor antibody entered Phase Ib/II clinical trials for treatment imaging different solid tumors. Here recent advances on biology pharmacology cancer, will be discussed.

Language: Английский

Citations

28
Design of novel anti-cancer drugs targeting TRKs inhibitors based 3D QSAR, molecular docking and molecular dynamics simulation DOI
Mohammed Er-rajy, Mohamed El fadili, Somdutt Mujwar

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 41(21), P. 11657 - 11670

Published: Jan. 25, 2023

Tropomyosin receptor kinase (TRK) enzymes are responsible for different types of tumors caused by neurotrophic tyrosine gene fusion and have been identified as an effective target anticancer therapy. The study the mechanism between polo-like (PLKs) pyrazol inhibitors was performed using 3D-QSAR modeling, molecular docking, MD simulations in order to design high-activity inhibitors. HQSAR (Q2 = 0.793, R2 0.917, R2ext 0.961), CoMFA 0.582, 0.722, 0.951), CoMSIA/SE 0.603, 0.801, 0.849), Topomer 0.726, 0.992, 0.717) showed good reliability predictability. All models successfully tested external validation, so all five established reliable. analysis contour maps gives structural information improve inhibitory function. Molecular docking results show that amino acids Met 592, GLU 590, LEU 657, VAL 524, PHE 589 active sites tropomyosin TRKs. obtained compound 19i could form a more stable complex protein (PDB id: 5KVT). Based on these results, we developed new compounds their expected activities. physicochemical ADME-Tox properties four proposed molecules orally bioavailable, they not toxic Ames test. Thus, would provide modeling help experimental researchers find TRK type I efficiently.Communicated Ramaswamy H. Sarma.

Language: Английский

Citations

37
QSAR, molecular docking, and molecular dynamics simulation–based design of novel anti-cancer drugs targeting thioredoxin reductase enzyme DOI
Mohammed Er-rajy, Mohamed El fadili, Somdutt Mujwar

et al.

Structural Chemistry, Journal Year: 2023, Volume and Issue: 34(4), P. 1527 - 1543

Published: Jan. 20, 2023

Language: Английский

Citations

25
Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity DOI

Samah Higazy,

Nermin Samir,

Ahmed El‐Khouly

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107089 - 107089

Published: Jan. 12, 2024

Language: Английский

Citations

12
Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery—An Updated Review on Their Multifaceted Therapeutic Applications (2020–2024) DOI Creative Commons

Xingyou Mo,

Devendra Pratap Rao,

Kirandeep Kaur

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(19), P. 4770 - 4770

Published: Oct. 9, 2024

Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview recent advances the evaluation indole-based last five years, highlighting roles cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, neurodegenerative management. shown significant efficacy targeting diverse pathways, making them valuable scaffolds designing new drugs. Notably, these demonstrated ability to combat drug-resistant cells pathogens, breakthrough field, offer promising options chronic diseases such as diabetes hypertension. By summarizing key findings exploring underlying mechanisms, this underscores potential indole addressing major healthcare challenges, thereby instilling hope optimism field modern medicine.

Language: Английский

Citations

10
Recent advances of anti-tumor nano-strategies via overturning pH gradient: alkalization and acidification DOI Creative Commons

Qiufang Gong,

Xuejiao Song, Yao Tong

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 24, 2025

The acidic tumor microenvironment, a hallmark of many solid tumors, is primarily induced by the high glycolytic rate cells. To avoid acidosis, cells ingeniously maintain an extracellular pH while keeping relatively alkaline intracellular pH. Overturning unique gradient has exhibited to be viable approach for cancer therapy. In this review, formation and regulatory mechanisms microenvironment in tumors will firstly outlined. Subsequently, we comprehensively summarize latest advancements anti-tumor therapy via using nanomedicines manipulate gradient, including acidifying environment alkalizing environment. Following this, discuss future potential strategies employing reverse gradient. This review aims foster research on therapeutic approaches targeting regulation holds optimistic outlook development field.

Language: Английский

Citations

1
Radiopharmaceuticals in nasopharyngeal Cancer DOI
Xiao‐Quan Xu, Xuemei Tang,

Wan-yin Wu

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 157, P. 108281 - 108281

Published: Feb. 14, 2025

Language: Английский

Citations

1
Preparation of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides and Their Experimental and Computational Biological Studies DOI Open Access
Mateusz Kciuk, Somdutt Mujwar, Anna Szymanowska

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 5892 - 5892

Published: May 24, 2022

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer properties. Investigated in this study, MM-compounds (MM134, MM136, MM137, and MM139) exhibited cytotoxic proapoptotic activity against cancer cell lines (BxPC-3, PC-3, HCT-116) nanomolar concentrations without causing cytotoxicity normal cells (L929 WI38). In silico predictions indicate that tested exhibit favorable pharmacokinetic profiles may exert through the inhibition BTK kinase, AKT-mTOR pathway PD1-PD-L1 interaction. Our findings point out these sulfonamide derivatives source new drugs after optimization.

Language: Английский

Citations

31
Association between pH regulation of the tumor microenvironment and immunological state DOI Creative Commons
Masahiro Hosonuma, Kiyoshi Yoshimura

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: July 10, 2023

The tumor microenvironment (TME) is characterized by interactions among various cells, including immune stromal and blood vessels mediated factors such as cytokines metabolites. development of cancer immunotherapy in recent years has facilitated a more comprehensive understanding the TME. TME changes with type host status, well therapeutic intervention. However, studies on pH regulation have been mostly based lactate, metabolite cells. Notably, Warburg effect results increased production secreted thereby acidifying extracellular affecting surrounding Lactate inhibits activation proliferation CD8+ T M1 macrophages, natural killer (NK) dendritic contributing to cell escape. It also involved angiogenesis tissue remodeling, promotes growth invasion. In this review, we discussed lactate-based cells its effects other constituent

Language: Английский

Citations

21