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Targeted Therapies: Perspectives of Chemical Synthesis and Molecular In Vivo Interactions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 6908

Special Issue Editors

Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Interests: Cancer signaling; Cancer immunology; Cancer metabolism; Targeted therapy; Repurposed drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cellular signaling varies between different pathophysiological conditions including diabetes, cancer, drug induced toxicity or heavy metal toxicity. It may also vary greatly between cell and tissue types. In modern era of molecular pharmacology “Targeted therapy” is the emerging concept to combat different pathophysiological conditions. Recent research projects are focused on identification of novel signaling pathways or the elucidation of the altered signaling crosstalk underlying a pathophysiological state. Researches are also focused on development of novel therapeutic strategies with novel drug candidates or by repurposing an existing drug specifically targeting a cellular pathway. The outcome of these projects is allowing the translational scientists to develop novel combinatorial therapeutic approach for better efficacy with minimal side effects. This could be a promising effort for management of different pathophysiological state with underlying disease conditions. This Special Issue of the International Journal of Molecular Sciences will focus on mechanism of molecular changes in different pathophysiological conditions (not limited to the ones stated above) and novel therapeutic approaches to combat the diseased state while considering pitfalls and future perspective.

Dr. Kalevi Kairemo
Dr. Pritam Sadhukhan
Guest Editors

Manuscript Submission Information

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Keywords

  • cancer therapeutics
  • diabetes
  • organ pathophysiology
  • chronic disease
  • targeted therapy
  • repurposed drugs
  • bioactive natural products

Published Papers (3 papers)

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Research

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24 pages, 7289 KiB  
Article
BTEAC Catalyzed Ultrasonic-Assisted Synthesis of Bromobenzofuran-Oxadiazoles: Unravelling Anti-HepG-2 Cancer Therapeutic Potential through In Vitro and In Silico Studies
by Ali Irfan, Ameer Fawad Zahoor, Azhar Rasul, Sami A. Al-Hussain, Shah Faisal, Sajjad Ahmad, Rida Noor, Muhammed Tilahun Muhammed and Magdi E. A. Zaki
Int. J. Mol. Sci. 2023, 24(3), 3008; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24033008 - 03 Feb 2023
Cited by 5 | Viewed by 2059
Abstract
In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line [...] Read more.
In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy. Full article
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23 pages, 5208 KiB  
Article
Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
by Mohamed Ayman El-Zahabi, Faida H. Bamanie, Salah Ghareeb, Heba K. Alshaeri, Moudi M. Alasmari, Mohamed Moustafa, Zohair Al-Marzooki and Mohamed F. Zayed
Int. J. Mol. Sci. 2022, 23(17), 9605; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179605 - 24 Aug 2022
Cited by 6 | Viewed by 1834
Abstract
New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant [...] Read more.
New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile. Full article
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Review

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14 pages, 1885 KiB  
Review
Androgen Receptor Imaging in the Management of Hormone-Dependent Cancers with Emphasis on Prostate Cancer
by Kalevi Kairemo and Marina Hodolic
Int. J. Mol. Sci. 2023, 24(9), 8235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098235 - 04 May 2023
Cited by 2 | Viewed by 2609
Abstract
Prostate cancer is dependent on the action of steroid hormones on the receptors. Endocrine therapy inhibits hormone production or blocks the receptors, thus providing clinical benefit to many, but not all, oncological patients. It is difficult to predict which patient will benefit from [...] Read more.
Prostate cancer is dependent on the action of steroid hormones on the receptors. Endocrine therapy inhibits hormone production or blocks the receptors, thus providing clinical benefit to many, but not all, oncological patients. It is difficult to predict which patient will benefit from endocrine therapy and which will not. Positron Emission Tomography (PET) imaging of androgen receptors (AR) may provide functional information on the likelihood of endocrine therapy response in individual patients. In this article, we review the utility of [18F]FDHT-PET imaging in prostate, breast, and other hormone-dependent cancers expressing AR. The methodologies, development, and new possibilities are discussed as well. Full article
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