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Recent Progress in Small Molecule Inhibitors as Targeted Cancer Therapy
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Recent Progress in Small Molecule Inhibitors as Targeted Cancer Therapy

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 11043

Special Issue Editors

Prof. Dr. Bahaa G.M. Youssif

E-Mail Website
Guest Editor
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
Interests: synthesis; organic; medicinal; chemistry; drug design; elucidation
Prof. Dr. Hesham AbdelAziz El-Beshbishy

E-Mail Website
Guest Editor
Medical Laboratory Sciences Department, Fakeeh College for Medical Sciences, P.O. Box 2537, Jeddah 21461, Saudi Arabia
Interests: oxidative stress; animal models of diseases; gene cloning; molecular biology; natural products; pollutants; molecular mechanistic study of diseases; toxicants; proteomics; human genetics; xenobiotics
Dr. Ahmed Safwat M. Aboraia

E-Mail Website
Guest Editor
Associate Professor, Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
Interests: medicinal chemistry; drug design; computer aided

Special Issue Information

Dear Colleagues,

Enzyme inhibitors are small molecules that inhibit the target protein's enzymatic activity. They inhibit major enzymes that act as signals for the development of cancer cells. Cancer cells can, thus, be prevented from developing and spreading if these cell signals are blocked. Because of their low molecular weight, these compounds can easily penetrate cells. Small molecule inhibitors can be derived from rational drug design leads or isolated from natural resources. A target-based drug discovery pathway typically includes target identification, target validation, hit identification, hit to lead, and lead optimization. Understanding the molecular interactions between small molecules and their targets is critical in drug discovery.

Small molecule inhibitors have emerged as a major therapeutic class for cancer treatment as a result of the identification of molecular targets and growing understanding of their cellular functions. Multitargeted and highly selective kinase inhibitors are used to treat advanced treatment-resistant cancers, and many have received regulatory approval for early clinical settings as adjuvant therapies or first-line options for recurrent or metastatic disease. The lessons learned from the development of these agents can be used to accelerate the development of next-generation inhibitors, with the goal of optimizing the therapeutic index, overcoming drug resistance, and establishing combination therapies.

Small molecule inhibitors have a bright future because they have the potential to investigate novel difficult-to-drug targets, to use predictive non-clinical models to select promising drug candidates for human evaluation, and to deliver precision medicine using dynamic clinical trial interventions with liquid biopsies.

This Special Issue is intended to bring together scientific papers on small molecule inhibitors derived from synthetic or natural pathways for cancer therapy. Studies on the design, synthesis, and structural elucidation of small molecule inhibitors as anticancer agents, as well as studies on possible mechanisms of action, docking simulations, ADMET studies, and any other relevant issues, can be discussed.

Prof. Dr. Bahaa G.M. Youssif
Prof. Dr. Hesham AbdelAziz El-Beshbishy
Dr. Ahmed Safwat M. Aboraia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • inhibitors
  • cancer
  • mechanistic
  • polypharmacology
  • aromatic
  • heterocycles
  • drug design
  • kinases
  • resistance

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Published Papers (3 papers)

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Research

17 pages, 2291 KiB  
Article
Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-b]indol-3-one Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways
by Lamya H. Al-Wahaibi, Anber F. Mohammed, Mostafa H. Abdelrahman, Laurent Trembleau and Bahaa G. M. Youssif
Molecules 2023, 28(3), 1269; https://doi.org/10.3390/molecules28031269 - 28 Jan 2023
Cited by 17 | Viewed by 3366
Abstract
Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-ones 5a–c derivatives as [...] Read more.
Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-ones 5a–c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a–e, 4a–c, and 5a–c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a–e, 4a–c, and 5a–c had significant antiproliferative activity with GI50 values ranging from 29 nM to 78 nM, with 3a–e outperforming 4a–c and 5a–c in their inhibitory actions against the tested cancer cell lines. Compounds 3a–e were tested for EGFR inhibition, with IC50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a–e had higher anti-BRAFV600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a–e revealed safety and good pharmacokinetic profile. Full article
(This article belongs to the Special Issue Recent Progress in Small Molecule Inhibitors as Targeted Cancer Therapy)
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25 pages, 7138 KiB  
Article
Biochemical Pilot Study on Effects of Pomegranate Seed Oil Extract and Cosmetic Cream on Neurologically Mediated Skin Inflammation in Animals and Humans: A Comparative Observational Study
by Asmaa Fathi Hamouda and Shifa Felemban
Molecules 2023, 28(2), 903; https://doi.org/10.3390/molecules28020903 - 16 Jan 2023
Cited by 13 | Viewed by 5047
Abstract
The presence of phenobarbital and formaldehyde in drugs, food, and beverages can lead to various health issues, including inflammation, oncogenesis, and neurological distress. Psychological stress leads to mood fluctuations and the onset of skin inflammation. Skin inflammation has a range of causes, including [...] Read more.
The presence of phenobarbital and formaldehyde in drugs, food, and beverages can lead to various health issues, including inflammation, oncogenesis, and neurological distress. Psychological stress leads to mood fluctuations and the onset of skin inflammation. Skin inflammation has a range of causes, including chemicals, heavy metals, infection, immune-related disorders, genetics, and stress. The various treatments for skin inflammation include medical and cosmetic creams, diet changes, and herbal therapy. In this study, we investigated the effects of Avocom-M and pomegranate seed oil extract (PSOE) against phenobarbital- and formaldehyde-induced skin biochemical changes in rats. We analyzed the constituents of PSOE using gas chromatography–mass spectrometry and inductively coupled plasma–mass spectrometry. We also observed biochemical changes in the skin of human volunteers with and without TROSYD and PSOE as a skin cream. We compared the biochemical changes in human volunteers’ skin before treatment and 21 days after the treatment stopped. The outcomes showed an improvement in the rats’ biochemical status, due to PSOE and Avocom-M treatment. The human volunteers treated with TROSYD and PSOE showed substantial amelioration of skin inflammation. PSOE, Avocom-M, and TROSYD produced beneficial effects by reducing the levels of cyclooxygenase-2, lipid peroxidation, tyrosinase, hyaluronidase, elastase, collagenase, and nitric oxide in the animals tested on and in human volunteers. Full article
(This article belongs to the Special Issue Recent Progress in Small Molecule Inhibitors as Targeted Cancer Therapy)
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18 pages, 4726 KiB  
Article
Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action
by Essmat M. El-Sheref, Mohamed A. Ameen, Kamal M. El-Shaieb, Fathy F. Abdel-Latif, Asmaa I. Abdel-naser, Alan B. Brown, Stefan Bräse, Hazem M. Fathy, Iqrar Ahmad, Harun Patel, Hesham A. M. Gomaa, Bahaa G. M. Youssif and Asmaa H. Mohamed
Molecules 2022, 27(24), 8765; https://doi.org/10.3390/molecules27248765 - 10 Dec 2022
Cited by 7 | Viewed by 2108
Abstract
Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a–e and 7a–e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a–e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained [...] Read more.
Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a–e and 7a–e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a–e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal–Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a–e and 7a–e were evaluated. Compounds 4a–e and 7a–e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids. Full article
(This article belongs to the Special Issue Recent Progress in Small Molecule Inhibitors as Targeted Cancer Therapy)
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