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Antiplatelet and Anti-inflammatory Agents: Synthesis, Structures, and Biological Evaluation

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

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 9763

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Prof. Dr. Philippopoulos Athanassios

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Department of Chemistry, National and Kapodistrian University of Athens, 157 84 Zografou, Greece
Interests: organometallic; coordination chemistry; renewable energy resources; dye sensitized solar cells for energy conversion; bio-inorganic chemistry; metal-based drugs; catalysis; transfer hydrogenation reactions

Special Issue Information

Dear Colleagues,

This Special Issue of Molecules, entitled “Antiplatelet and anti-inflammatory agents. Synthesis, structural characterization and biological evaluation”, aims to focus on recent research and review articles within the field of antiplatelet and anti-inflammatory drugs. Both biological manifestations are interconnected, and the need for new compounds exerting these potencies remains.

Targeting platelets, thrombin, and other inflammatory mediators is a realistic means to prevent acute thromboembolic artery occlusions in cardiovascular diseases and treat chronic inflammatory diseases. Current antiplatelet drugs include the classic aspirin and thienopyridine analogs (clopidogrel, ticlopidine), and their combinations thereof, which exert undesirable side effects such as bleeding complications, etc. The development of safer, next-generation antiplatelet drugs is of high priority. Future developments include more selective inhibitors of ADP, thrombin, along with new thrombotic mediators such as platelet-activating factor (PAF) and collagen. Anti-collagen drug compounds have recently been described as modern anti-thrombotic approaches with less bleeding risk compared to traditional antithrombotic approaches.

Within this call, emphasis is given on the different categories of molecular compounds displaying the aforementioned biological activities. Investigation of small molecules, mainly organic compounds, covers this huge research area to a great extent. This expands to a wide variety of compounds including natural products, synthetic organic molecules, and metal ions. Theoretical calculations (molecular docking) are a helpful tool.

Recently, a new sub-topic has emerged—so-called metal-based antiplatelet compounds, revealing the great potencies of the metal-based compounds toward this goal. Notably, the anti-inflammatory activities of metal-based compounds have been described to a lesser extent. All these issues highlight the need for new molecular compounds (organic and transition metal complexes) that could be incorporated into the therapeutic armamentarium.

Readers of this Special Issue will be informed about the recent progress in a cutting-edge research area with a high public health impact. Cardiovascular diseases and thrombosis are the leading causes of death worldwide. Therefore, contributions within the frame of this call will be highly appreciated.

Prof. Dr. Philippopoulos Athanassios
Guest Editor

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Published Papers (4 papers)

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Research

18 pages, 6569 KiB

Open AccessArticle

Identification of Novel Cyclooxygenase-1 Selective Inhibitors of Thiadiazole-Based Scaffold as Potent Anti-Inflammatory Agents with Safety Gastric and Cytotoxic Profile

by Michelyne Haroun, Maria Fesatidou, Anthi Petrou, Christophe Tratrat, Panagiotis Zagaliotis, Antonis Gavalas, Katharigatta N. Venugopala, Hafedh Kochkar, Promise M. Emeka, Nancy S. Younis, Dalia Ahmed Elmaghraby, Mervt M. Almostafa, Muhammad Shahzad Chohan, Ioannis S. Vizirianakis, Aliki Papadimitriou-Tsantarliotou and Athina Geronikaki

Molecules 2023, 28(8), 3416; https://doi.org/10.3390/molecules28083416 - 12 Apr 2023

Cited by 1 | Viewed by 1685

Abstract

Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC₅₀ values of the three most active compounds 3, 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3, 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents. Full article

(This article belongs to the Special Issue Antiplatelet and Anti-inflammatory Agents: Synthesis, Structures, and Biological Evaluation)

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20 pages, 2033 KiB

Open AccessArticle

Tin(II) and Tin(IV) Complexes Incorporating the Oxygen Tripodal Ligands [(η⁵-C₅R₅)Co{P(OEt)₂O}₃]⁻, (R = H, Me; Et = -C₂H₅) as Potent Inflammatory Mediator Inhibitors: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin

by Alexandros Kalampalidis, Artemis Damati, Demetrios Matthopoulos, Alexandros B. Tsoupras, Constantinos A. Demopoulos, Gregor Schnakenburg and Athanassios I. Philippopoulos

Molecules 2023, 28(4), 1859; https://doi.org/10.3390/molecules28041859 - 16 Feb 2023

Cited by 1 | Viewed by 1599

Abstract

Metal complexes displaying antiplatelet properties is a promising research area. In our methodology, Platelet-Activating Factor (PAF), the most potent lipid pro-inflammatory mediator, serves as a biological probe. The antiplatelet activity is exerted by the inhibition of the PAF-induced aggregation in washed rabbit platelets (WRPs) and in rabbit plasma rich in platelets (rPRPs). Herein, the synthesis and biological investigation of a series of organometallic tin(II) and tin(IV) complexes, featuring the oxygen tripodal Kläui ligands [(η⁵-C₅R₅)Co{P(OEt)₂O}₃]⁻, {R = H, (L_OEt⁻); Me (L*_OEt⁻)}, are reported. Reaction of NaL_OEt (1a) and NaL*_OEt (1b) with SnCl₂, yielded the rare four-coordinate L_OEtSnCl (2a) and L*_OEtSnCl (2b) complexes. Accordingly, L_OEtSnPh₃ (3a) and L*_OEtSnPh₃ (3b) were prepared, starting from Ph₃SnCl. Characterization includes spectroscopy and X-ray diffraction studies for 2a, 2b and 3b. The antiplatelet activity of the lead complexes 2b and 3a (IC₅₀ = 0.5 μΜ) is superior compared to that of 1a and 1b, while both complexes display a pronounced inhibitory activity against thrombin (IC₅₀ = 1.8 μM and 0.6 μM). The in vitro cytotoxic activities of 3a and 2b on human Jurkat T lymphoblastic tumor cell line is higher than that of cisplatin. Full article

(This article belongs to the Special Issue Antiplatelet and Anti-inflammatory Agents: Synthesis, Structures, and Biological Evaluation)

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18 pages, 2828 KiB

Open AccessArticle

A Novel Approach to Unraveling the Apoptotic Potential of Rutin (Bioflavonoid) via Targeting Jab1 in Cervical Cancer Cells

by Pratibha Pandey, Fahad Khan, Faisal Abdulrahman Alzahrani, Huda A. Qari and Mohammad Oves

Molecules 2021, 26(18), 5529; https://doi.org/10.3390/molecules26185529 - 12 Sep 2021

Cited by 13 | Viewed by 3127

Abstract

Rutin has been well recognized for possessing numerous pharmacological and biological activities in several human cancer cells. This research has addressed the inhibitory potential of rutin against the Jab1 oncogene in SiHa cancer cells, which is known to inactivate various tumor suppressor proteins including p53 and p27. Further, the inhibitory efficacy of rutin via Jab1 expression modulation in cervical cancer has not been yet elucidated. Hence, we hypothesized that rutin could exhibit strong inhibitory efficacy against Jab1 and, thereby, induce significant growth arrest in SiHa cancer cells in a dose-dependent manner. In our study, the cytotoxic efficacy of rutin on the proliferation of a cervical cancer cell line (SiHa) was exhibited using MTT and LDH assays. The correlation between rutin and Jab1 mRNA expression was assessed by RT-PCR analysis and the associated events (a mechanism) with this downregulation were then explored via performing ROS assay, DAPI analysis, and expression analysis of apoptosis-associated signaling molecules such as Bax, Bcl-2, and Caspase-3 and -9 using qRT-PCR analysis. Results exhibit that rutin produces anticancer effects via inducing modulation in the expression of oncogenes as well as tumor suppressor genes. Further apoptosis induction, caspase activation, and ROS generation in rutin-treated SiHa cancer cells explain the cascade of events associated with Jab1 downregulation in SiHa cancer cells. Additionally, apoptosis induction was further confirmed by the FITC-Annexin V/PI double staining method. Altogether, our research supports the feasibility of developing rutin as one of the potent drug candidates in cervical cancer management via targeting one such crucial oncogene associated with cervical cancer progression. Full article

(This article belongs to the Special Issue Antiplatelet and Anti-inflammatory Agents: Synthesis, Structures, and Biological Evaluation)

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15 pages, 1905 KiB

Open AccessArticle

Influence of Vincristine, Clinically Used in Cancer Therapy and Immune Thrombocytopenia, on the Function of Human Platelets

by Li-Ming Lien, Wan-Jung Lu, Kuan-Hung Lin, Ling-Hsuan Kang, Ting-Yu Chen, Bo-Jung Lin, Yung-Chang Lu, Chun-Yao Huang, Chun-Ming Shih, Hsuan Chen, Yao-Chou Tsai, Ray-Jade Chen and Joen-Rong Sheu

Molecules 2021, 26(17), 5340; https://doi.org/10.3390/molecules26175340 - 2 Sep 2021

Cited by 3 | Viewed by 2534

Abstract

Vincristine is a clinically used antimicrotubule drug for treating patients with lymphoma. Due to its property of increasing platelet counts, vincristine is also used to treat patients with immune thrombocytopenia. Moreover, antiplatelet agents were reported to be beneficial in thrombotic thrombocytopenic purpura (TTP). Therefore, we investigated the detailed mechanisms underlying the antiplatelet effect of vincristine. Our results revealed that vincristine inhibited platelet aggregation induced by collagen, but not by thrombin, arachidonic acid, and the thromboxane A₂ analog U46619, suggesting that vincristine exerts higher inhibitory effects on collagen-mediated platelet aggregation. Vincristine also reduced collagen-mediated platelet granule release and calcium mobilization. In addition, vincristine inhibited glycoprotein VI (GPVI) signaling, including Syk, phospholipase Cγ2, protein kinase C, Akt, and mitogen-activated protein kinases. In addition, the in vitro PFA-100 assay revealed that vincristine did not prolong the closure time, and the in vivo study tail bleeding assay showed that vincristine did not prolong the tail bleeding time; both findings suggested that vincristine may not affect normal hemostasis. In conclusion, we demonstrated that vincristine exerts antiplatelet effects at least in part through the suppression of GPVI signaling. Moreover, this property of antiplatelet activity of vincristine may provide additional benefits in the treatment of TTP. Full article

(This article belongs to the Special Issue Antiplatelet and Anti-inflammatory Agents: Synthesis, Structures, and Biological Evaluation)

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