key: cord-0730745-7fxwjx56
authors: Srour, Aladdin M.; Panda, Siva S.; Mostafa, Ahmed; Fayad, Walid; El-Manawaty, May A.; A. F. Soliman, Ahmed; Moatasim, Yassmin; El Taweel, Ahmed; Abdelhameed, Mohamed F.; Bekheit, Mohamed S.; Ali, Mohamed A.; Girgis, Adel S.
title: Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties
date: 2021-11-04
journal: Bioorg Chem
DOI: 10.1016/j.bioorg.2021.105466
sha: 6358e45fcf3f0b5d2ca43fd67fea19db8d5e396a
doc_id: 730745
cord_uid: 7fxwjx56

Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells.

Natural products are still the main resources of human needs. Many therapeutics were designed due to inspiration of the biologically active natural compounds [1] .

Curcumin is a natural compound (isolated from Curcuma longa) [2] gained interest due to its broad range biological properties as anti-inflammatory [3] , anticancer [4] [5] [6] and antimicrobial [7] . Although its safety profile, the clinical applications are hindered due to its bioavailability (low aqueous or plasma solubility and stability at physiological pH) [8, 9] . This is why curcumin mimics were alternatively considered by many researchers. It is believed that the active methylene connecting the β-diketonic moieties plays a crucial role in curcumin stability [10, 11] . The diene connected through a carbonyl group forming a five-carbon system seems an acceptable approach for developing a biologically enhanced scaffold [12] [13] [14] . 3,5-Diylidene-4-piperidones are curcumin mimics with broad promising biological properties of which antitumor against diverse cancer cell lines [15] [16] [17] [18] and antiinflammatory [19] . The present study deals with synthesis of 3,5-bis(arylidene)-4piperidones as curcumin mimics conjugated with acetylsalicylic acid (aspirin) (Fig. 1) . Since the discovery of aspirin by Felix Hoffman of Bayer industry (1897), it became one of the most usable low-cost NSAIDs (non-steroidal anti-inflammatory drugs) worldwide, accessible as an analgesic and anti-inflammatory therapeutic [20, 21] . It has been also reported that, daily low dose aspirin reduces heart attack risks [22] .

Gastrointestinal ulcer is the most serious drawback of aspirin similar to many other NSAIDs [23] . This is attributable to the irritation formed due to direct contact of the NSAID carboxylic group with the tissue(s) producing prostaglandin [24] . Enteric-coated aspirin was considered to overcome the gastrointestinal ulceration side effects but the reduced efficacy especially in chronic administration and coronary heart disease hindered the applicability [25, 26] . Many reports mentioned that aspirin can reduce the risk of cancer [27] [28] [29] [30] [31] [32] [33] and inhibit NFҡβ signal which may assist in cancer growth and metastasis [34, 35] . This is why many researchers adopted investigation of aspirin based-analogues as potential antitumor candidates [36] [37] [38] [39] . Others considered conjugation of aspirin with antitumor chemotherapeutics [40] because inflammation initiated by cancer may lead to metastasis [41] . Furthermore, the reported antitumor properties of salicylamide-containing compounds [42] [43] [44] prompted the current study due to the targeted salicylamide derivative formed through conjugation of the carboxylic group of aspirin with the nitrogen atom of piperidinyl heterocycle. Recent reports describing the pathophysiological role of COX-1/2 inhibitors in cancer disease and the discovered COX-2 inhibitors as antitumor also supported the rational of the current study [45, 46] .

Although the continuous advances/efforts in diagnosis and treatment in cancer research, it is still one of the most serious challenges for human health. It is the second cause of death globally after cardiovascular diseases [47] . It is expected the number of deaths will exceed those of any other disease and be the first cause of human mortality within few years [48] . Needs for more therapeutic approaches especially, new chemotherapies with higher efficacies and fewer drawbacks are still in demand. The designed agents of the current study will be considered for antitumor evaluation against HCT116 (colon), MCF7 (breast) and A431 (squamous skin) cancer cell lines. Selection of the mentioned cancer cell lines among many other types are due to promising properties reported by the piperidone-containing compounds [15, 16, 49] . Colorectal (including colon and rectum) cancer is the third leading cause of death globally among all cancer types. The five year survival due to colon cancer is still high (30%) due to the recurrence and metastasis [50] . Many factors are overlapped in colon cancer including heredity, colon polyps, and ulcerative colitis. Colon cancer usually arises from colon polyps [49] . Surgery is the most accepted optional approach for localized colon cancer. However, chemotherapy is the most successful for metastasis [51] . Breast cancer is the fifth cause of human cancer death and the second for women [52, 53] . Surgery, chemotherapy, radiotherapy, immunotherapy and hormone therapy, are still the main options for breast cancer [53, 54] .

Skin cancer incidence and mortality are increased in the last few years [55] . This is attributed to many factors including exposure to sunlight (ultraviolet radiation) [56] and genetic predisposition [57] . Skin cancers are of two main types, melanoma and nonmelanoma (basal and squamous) cell carcinoma. Although the non-melanoma cancers are the more prevalent, melanoma skin cancer is more aggressive with a higher number of deaths [58] . [63] . The scientific society with the pharmaceutical companies did their best for developing vaccine(s) that may control the viral prophylactic action and identifying/developing therapeutic agent(s) for infected patients. For optimizing an effective medication computational technique or drug re-proposing were utilized to accelerate the identification of the urgent needs [59, 64, 65] . Many drugs were reproposed/adopted for COVID-19 of which Lopinavir/Ritonavir, Chloroquine, Hydroxychloroquine, Arbidol, Remdesivir and Favipiravir ( Fig. 2 ) but none of them seems of high efficacy especially for advanced infection [60, [66] [67] [68] . This is why new effective agents are still in demand. Due to the reports mentioned for the anti-SARS-CoV-2 properties of diverse antitumor active agents [69] [70] [71] , the targeted conjugates within the current study will be intended for anti-SARS-CoV-2 properties investigation. The successful clinical reports for treating the colon cancer patients with antiviral drugs alone or with antitumor drugs [72] also add good support for the aim of the present study directed towards optimizing new hits of dual functions as antitumor and anti-SARS-CoV-2 with safety properties against normal cells. Recent reports describing aspirin as anti-SARS-CoV-2 with mild properties and safe applicability also prompted the current study [73] . 

The acid chlorides 3a,b [74, 75] were obtained from the corresponding acetylsalicylic acids 2a,b [76] by the reported procedure [oxalyl chloride in dichloromethane containing a catalytic amount of N-N-dimethylformamide (DMF)].

Reaction of the 3E, 5E-bis(arylidene)-4-piperidones 4a-i [15, 16, [77] [78] [79] with the appropriate 3a,b in DMF in presence of sufficient amount of triethylamine in an ice-cold water bath afforded the targeted conjugates 5a-p in acceptable yields (60-88 %) (Scheme 1). IR spectrum of 5a (an example of the targeted family) reveals the piperidinyl ketonic and salicylate amidic carbonyls at ν = 1767, 1643 cm -1 , respectively. 1 H-NMR spectrum of 5a shows the piperidinyl methylene protons as singlet signals at δ H = 4.58, 5.01 and the salicylate singlet acetyl protons at δ H = 2.14. However, the exocyclic olefinic methine protons are hidden under the aromatic protons. 13 

The standard MTT bioassay technique was considered for antiproliferation properties determination of the synthesized agents 5a-p [80] . Based on the antiproliferative properties notable SARs (structure-activity relationships) could be attained. Attachment of the salicylate ring with a chlorine atom/substituent enhances the observed antiproliferation properties (compound 5i is an exception). The number of methoxy groups attached to the exocyclic benzylidene system is also a controlling factor for the exhibited bio-properties. The high number of methoxy groups, the higher potency of the tested agent as revealed by compounds 5f/5g/5h (IC 50 = 6.042, 0.973, 0.472 μM for 5f, 5g and 5h, respectively) and 5m/5n/5o (IC 50 = 3.811, 0.444, 0.431 μM for 5m, 5n and 5o, respectively).

Compounds 5o and 5c are the most potent agents synthesized against MCF7 cell line with 1.19, 1.12 folds relative to the standard reference, 5-fluorouracil (IC 50 = 2.653, 2.806, 3.15 μM for 5o, 5c and 5-fluorouracil, respectively). SAR can be concluded due to the antiproliferative bio-observations. It is noticed that the 5-chlorosalicylate-containing compounds show better antiproliferative properties than the unsubstituted analogues (compounds 5c and 5i are exceptions). It is also noticed that, increment the number of methoxy groups attached to the benzylidene ring is associated with enhancement of the shown bio-efficacies as shown by compounds 5f/5g/5h and 5m/5n/5o. 5f/5g/5h (IC 50 = 6.083, 2.389, 1.333 μM for 5f, 5g and 5h, respectively) and 5m/5n/5o (IC 50 = 5.944, 1.486, 0.750 μM for 5m, 5n and 5o, respectively). Surprisingly, high compatibility was noticed due to the SARs of all the tested cell lines.

Safe profile of the potent agents was established upon testing against RPE1 (noncancer, retinal pigment epithelium) cell line (Table 1) . [15, 16] , c 5-FU = 5flurouracil [15, 16] , d NT = not tested.

Flow cytometric analysis is an accessible and rapid technique used intensively in medicinal chemical studies for assigning the cell cycle progress of living cells. The detected fluorescence levels estimate quantitatively the DNA content hence; determine the progress of cell cycle [80, 85] . Compounds 5c and 5o (the most promising agents synthesized with high potency against HCT116) were selected for flow cytometric analysis studies applying the IC 50 value of each respective agent observed through MTT bio-assay, to identify their impact on the progress of cell cycle and accessibility for induction of apoptosis and/or necrosis.

From the results obtained ( 

The anti-SARS-CoV-2 properties of the synthesized aspirin-curcumin mimic conjugates were determined by the standard technique ( 

Targeted cancer chemotherapy is an important approach for competing cancer adopted intensively for reducing the side effects of other agents that many interfere with crucial cellular processes/targets or mistargeting the aimed protein/receptor [88, 89] .

Tyrosine kinases are classes of proteins participate in many biochemical activities controlling diverse cellular processes of which cell proliferation, differentiation and death [90] . Overexpression of protein kinases may lead to tumor invasion or metastasis. This explains the interest in tyrosine kinase inhibitors as chemotherapeutical agents. Tyrosine kinases usually classify to receptor and non-receptor tyrosine kinases. The receptor tyrosine kinases include many growth factors of which vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) that constitute important targets for developing antitumor drugs [90] .

Multi-targeted tyrosine kinase inhibitors can be more potent, wider applicable agents against different cancer types and achieve satisfactory therapeutic effects [91] .

Since, cancer initiation and progression usually depends on several receptor or singling pathways, the multi-targeted agents seem more appropriate with several advantages over the mono-targeted therapies [92] .

Angiogenesis (formation of new blood vessels from the pre-existing ones) is a

physiological key for many solid tumor proliferation and metastasis. VEGF which is secreted by the malignant tumor plays an important role in the angiogenic process [93] .

Three main types have been identified for vascular endothelial growth factor receptors;

VEGFR-1, VEGFR-2, and VEGFR-3 which are cell surface protein modulating angiogenesis tyrosine kinase receptors [94] [95] [96] . VEGFR-2 is identified as the main receptor suppressing angiogenesis and inhibiting solid tumor proliferation [97] .

The VEGFR-2 inhibitory properties of the synthesized aspirin-curcumin mimic conjugates are represented in Table 5 Generally, most of the tyrosine kinase inhibitory properties (VEGFR-2 and EGFR)

of MCF7 and HCT116 cell lines support the antiproliferation properties discovered of the synthesized conjugates ( Table 1 ). The slight differences due to the antiproliferation properties and tyrosine kinase inhibitory properties can be attributed to the applied conditions due to the standard techniques. 

Inflammation is a natural response due to any harmful stimuli, infection or injury to human body [103] . It is usually associated with many serious diseases of which, rheumatoid arthritis [104] , asthma [105] , carcinoma [106] , bacterial/viral infections [107] .

Biochemical oxidation of arachidonic acid leads to the formation of prostaglandins and leukotrienes. Excessive formation of the latters is associated with inflammation, fever or pain [108] . Cyclooxygenase (COX) enzymes are responsible for biochemical transformation of arachidonic acid to prostaglandins. Cyclooxygenases are of three isoforms (COX-1, -2 and -3). COX-1 is a constitutive enzyme for normal cells producing prostaglandins of many important physiological functions such as renal blood flow and gastrointestinal mucous production [109] while, COX-2 is an inducible enzyme in the endothelial cells. COX-3 is another isoform mostly present in the cerebral cortex and heart [110] . Many traditional NSAIDs such as aspirin express their action through roughly inhibition of both COX-1 and COX-2. COX-2 selective drugs are already discovered within the last few decades (e.g. Celecoxib, Rofecoxib and Valdecoxib) (Fig. 7) . However, accessibility as medication is now questionable due to their serious cardiovascular side effects discovered [111] . This is why new anti-inflammatory agents with high efficacy and limited side effects are still in demand. The COX-1/2 inhibitory properties of the synthesized agents and aspirin (standard reference) are presented in Table 6 which determined by the standard technique [112, 113] .

It is noticeable that all the synthesized agents show enhanced COX-1/2 properties (IC 50 50 is the concentration of a tested agent for the 50% inhibition of COX-1, COX-2. 

A series of piperidone-salicylate conjugates 5a-p were synthesized in acceptable Many of the synthesized agents show enhanced COX-1/2 properties with higher selectivity index towards COX-2 relative to COX-1 than aspirin (standard reference). The possible applicability of the potent agents discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal cells (RPE1 and VERO-E6).

Melting points were determined on a capillary point apparatus (Stuart SMP3) equipped with a digital thermometer. IR spectra (KBr) were recorded on a Shimadzu FT-IR 8400S spectrophotometer. Reactions were monitored using thin layer chromatography (TLC) on 0.2 mm silica gel F254 plates (Merck) utilizing various solvents for elution. The chemical structures of the synthesized compounds were characterized by nuclear magnetic resonance spectra ( 1 H-NMR, 13 C-NMR) and determined on a Bruker NMR spectrometer (500 MHz, 125 MHz for 1 H and 13 C, respectively). 13 C-NMR spectra are fully decoupled.

Chemical shifts were reported in parts per million (ppm) using the deuterated solvent peak or tetramethylsilane as an internal standard.

The appropriate acid chloride of aspirin 3a,b (2.5 mmol) in DMF (5 ml containing sodium chloride (1 g) was collected, washed with tap water and crystallized from a suitable solvent affording 5a-p.

It was obtained from the reaction of 3a and 4a as pale yellow microcrystals from ethanol with mp 171-173 °C and yield 72% (0.79 g 

It was obtained from the reaction of 3a and 4b as colorless microcrystals from light 

It was obtained from the reaction of 3a and 4c as yellow microcrystals from methanol with 

It was obtained from the reaction of 3a and 4g as yellow microcrystals from methanol with 

It was obtained from the reaction of 3a and 4h as colorless microcrystals from methanol 

It was obtained from the reaction of 3b and 4a as pale yellow microcrystals from n-butanol 

It was obtained from the reaction of 3b and 4f as yellow microcrystals from n-butanol with mp 

Details of the experimental techniques utilized for biological studies were mentioned in the supplementary file.

The modification of natural products for medical use

Recent developments in chemistry and biology of curcumin analogues

Biological evaluation and molecular docking studies of new curcuminoid derivatives: Synthesis and characterization

Synthesis, evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms

Recent advances of curcumin and its analogues in breast cancer prevention and treatment

Curcumin induces cell death of human papillary thyroid carcinoma BCPAP cells through endoplasmic reticulum stress

Cytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: Inhibition of histone acetylation and generation of reactive oxygen species

Pharmacodynamic and pharmacokinetic study of oral curcuma extract in patients with colorectal cancer

Synthesis and biological evaluation of curcumin inspired indole analogues as tubulin polymerization inhibitors

Synthesis and biological evaluation of allylated monocarbonyl analogues of curcumin (MACs) as anti-cancer agents for cholangiocarcinoma

Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues

Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and biological evaluation as potential anticancer agents

Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E 2 production in LPS-induced murine and human macrophages cell lines

Optimization of diarylpentadienones as chemotherapeutics for prostate cancer

Synthesis, human topoisomerase IIα inhibitory properties and molecular modeling studies of anti-proliferative curcumin mimics

Novel curcumin inspired antineoplastic 1-sulfonyl-4-piperidones: Design, synthesis and molecular modeling studies

Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines

Discovery of monocarbonyl curcumin hybrids as a novel class of human DNA ligase I inhibitors: in silico design, synthesis and biology

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

Aspirin: Bitter pill or miracle drug?

Collaborative overview of randomised trials of antiplatelet therapy. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies

Synthesis and anti-inflammatory evaluation of some new acylhydrazones bearing 2-aryl-thiazole

Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis

Enteric-coated aspirin in cardiac patients: Is it less effective than plain aspirin?

Long-term use of low-dose aspirin for cancer prevention: A 10-year population cohort study in Hong Kong

Association between aspirin use and risk of hepatocellular carcinoma

Association of analgesic use with risk of ovarian cancer in the nurses' health studies

Aspirin and colorectal cancer: The promise of precision chemoprevention

Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials

Association of aspirin and nonsteroidal anti-inflammatory drug use with breast cancer

Aspirin and non-steroidal antiinflammatory drugs for cancer prevention: An international consensus statement

The anti-inflammatory agents aspirin and salicylate inhibit the activity of IҡB kinase-β

Inhibition of NF-kappa B by sodium salicylate and aspirin

Novel resveratrol-based aspirin prodrugs: Synthesis, metabolism, and anticancer activity

A novel aspirin prodrug inhibits NFκB activity and breast cancer stem cell properties

Synthesis and biological evaluation of salicylic acid conjugated isoxazoline analogues on immune cell proliferation and angiogenesis

Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid

The prodrug platin-A: Simultaneous release of cisplatin and aspirin

True or false? Challenges and recent highlights in the development of aspirin prodrugs

SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway

Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine

Synthesis and biological evaluation of N-aryl salicylamides with a hydroxamic acid moiety at 5-position as novel HDAC-EGFR dual inhibitors

Cyclooxygenase-1 (COX-1) and COX-1 inhibitors in cancer: A review of oncology and medicinal chemistry literature

Preparation, COX-2 inhibition and anticancer activity of sclerotiorin derivatives

Recent progress in small molecule agents for the targeted therapy of triple-negative breast cancer

Small-molecule inhibitors of breast cancerrelated targets: Potential therapeutic agents for breast cancer

Katritzky, Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids

LncRNA KLK8 modulates stem cell characteristics in colon cancer

Colorectal cancer -review

Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triplenegative breast cancer

Recent advances in the treatment of breast cancer

Advances in novel drug delivery strategies for breast cancer therapy

Skin cancer: Epidemiology, disease burden, pathophysiology, diagnosis and therapeutic approaches

Sun-protective behaviors in populations at high risk for skin cancer

Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer

Synthesis, inverse docking-assisted identification and in vitro biological characterization of Flavonol-based analogs of fisetin as c-Kit, CDK2 and mTOR inhibitors against melanoma and nonmelanoma skin cancers

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review

Potential treatment methods targeting 2019-nCoV infection

Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic

A perspective on potential target proteins of COVID-19: Comparison with SARS-CoV for designing new small molecules

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papainlike protease (PLpro) inhibitors

Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking

The race to treat COVID-19: Potential therapeutic agents for the prevention and treatment of SARS-CoV-2

Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches

Natural products' role against COVID-19

Anticancer drugs and COVID-19 antiviral treatments in patients with cancer: What can we safely use?

Repurposing of anticancer drugs expands possibilities for antiviral and anti-inflammatory discovery in COVID-19

A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities

Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

FDA-approved drugs with potent in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2

Synthesis of novel SN38-aspirin prodrugs for the treatment of hepatocellular carcinoma

Development of 5-nitrothiazole derivatives: Identification of leads against both replicative and latent Mycobacterium tuberculosis

Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 integrase inhibitors

A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

Discovery and evaluation of piperid-4-one-containing mono-carbonyl analogs of curcumin as anti-inflammatory agents

3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2

Analysis of apoptosis by propidium iodide staining and flow cytometry

New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2

New pyrazine conjugates: Synthesis, computational studies, and antiviral properties against SARS-CoV-2

Current molecular-targeted therapies in NSCLC and their mechanism of resistance

Thiazole in the targeted anticancer drug discovery

The synthesis review of the approved Tyrosine kinase inhibitors for anticancer therapy in

Multi-targeted anticancer agents

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm

Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: Synthesis, structureactivity relationships, and antitumor activities of N-Phenyl-Nˈ-{4-(4-quinolyloxy)phenyl}ureas

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti-and pro-angiogenic therapies

VEGF receptor signaling in control of vascular function

Discovery of novel potent VEGFR-2 inhibitors exerting significant antiproliferative activity against cancer cell lines

Clinical advances in the development of novel VEGFR2 inhibitors

Advances in targeting epidermal growth factor receptor signaling pathway in mammary cancer

ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics

Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms

Inflammatory responses and inflammation-associated diseases in organs

Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

Type 2 inflammation in asthmadpresent in most, absent in many

Inflammation and cancer

Inflammation 2010: new adventures of an old flame

Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity

The Biology of Prostaglandin Synthesis and Inhibition

Phenolic compounds with radical scavenging and cyclooxygenase-2 (COX-2) inhibitory activities from Dioscorea opposite

Synthesis and pharmacological evaluation of N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide as cyclooxygenase inhibitors

COX-1 Inhibitor Screening Kit (Fluorometric)

Target binding properties and cellular activity of

BIBW 2992), an irreversible ErbB family blocker

X The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work

This work was supported financially by National Research Centre, Egypt, project ID: 12060101.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper