Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

Carullo, Gabriele; Galligano, F.; Aiello, Francesca

doi:10.1039/c6md00569a

Cited by 56 publications

(42 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A preliminary docking study was performed to provide an insight into the interaction of the naproxen-dehydrodipeptide scaffold with the active site of the COX-1 and COX-2 isoenzymes [29,30] (Figure 7, Table 2). The crystal structures of COX-1 and COX-2 enzymes show a high degree of sequence homology (~60%), but, nevertheless, there are key differences between the active sites [39,40]. The Ile-434 and Ile-523 residues of COX-1 are switched for smaller valine residues in COX-2 [39].…”

Section: Effect Of the Compounds On Cox-1/cox-2 Activitymentioning

confidence: 99%

Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

et al. 2020

View full text Add to dashboard Cite

The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen–dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.

show abstract

Section: Effect Of the Compounds On Cox-1/cox-2 Activitymentioning

confidence: 99%

Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

et al. 2020

View full text Add to dashboard Cite

show abstract

“…К настоящему времени накоплено достаточно данных о вовлеченности его в процесс канцерогенеза [23]. Показано защитное действие ингибиторов COX-2 в колитассоциированном опухолегенезе и при ряде других локализаций [24].…”

Section: экспериментальные статьиunclassified

Differences in the profile of cytokine expression induced by implantation of oncogenic and non-oncogenic millipore filters

2019

View full text Add to dashboard Cite

Background. Clarification of the mechanisms of carcinogenesis induced by foreign bodies is one of the urgent problems of modern oncology. This is due to the fact that there is a relationship between the processes of inflammation and carcinogenesis. Today, there is no doubt the fact that cytokines and signal molecules in the focus of inflammation (products of inflammation) can contribute to the initiation of carcinogenesis, as well as stimulate tumor progression. In the case of carcinogenesis induced by foreign bodies, the key issue is understanding the differences in the body’s response to the implantation of foreign bodies that can cause tumor formation and do not have this ability. One of the phenomena of this type of carcinogenesis is the occurrence of sarcoma after the subcutaneous implantation in mice of hydrophilic millipore filters with a pore diameter not exceeding 0.1 μm and the inability to induce tumors of one’s with a pore diameter greater than or equal to 0.22 μm.The objective of our work was to study the differences between oncogenic and non-oncogenic filters at the molecular level.Materials and methods. Reverse transcription polymerase chain reaction method was used to study the expression of a number of cytokines that are products of macrophage cells that live on the surface of implanted filters and in the surrounding capsule. Filters with pore diameters of 0.025 μm (carcinogenic) and 0.45 μm (non-carcinogenic) were compared in 8, 35 days and 5.5 months after implantation.Results and conclusion. After 8 days we observed significant (p <0.01) excess of expression of two cytokines interleukin 1β (IL-1β) by cells around oncogenic filters (with pore of 0.025 μm) compared to non-oncogenic one’s (with pore of 0.45 μm) After 35 days, significant (p <0.01) excess of expression of IL-1β, Tnf-α, iNOS (induced nitric oxide synthase), and IL-6 by cells around the oncogenic filters (0.025 μm) compared to non-oncogenic one’s (0.45 μm) was observed. There was no quantitative difference in the expression of Nf-κB1 and Nf-κB2 (nuclear factor κ-B1, κ-B2), Tgf-β (transforming growth factor β), IL-10. After 5.5 months the expression of IL-1β by cells on oncogenic filters was still significant; for Tnf-α, iNOS, IL-6 and IL-10 there was no practically difference in expression. For Nf-κB1 and Nf-κB2, Tgf-β and COX-2 (cyclooxygenase 2) the difference was significant, cells on non-oncogenic filters are expressed more then on oncogenic one’s.

show abstract

“…Studying the structures of most selective COX-2 inhibitors revealed the presence of diaryl substitution on carbocyclic or heterocyclic core ( Figure 1). Moreover, structure-activity relationship (SAR) studies of COXIBs showed that a COX-2 selectivity raised due to a hydrophobic interaction with an extra hydrophobic region and polar interactions with a secondary polar pocket that are found in COX-2 isozyme [18]. Moreover, the presence of electron withdrawing group in one of the aryl substitutions in the para position is more preferable than corresponding electron donating group [18].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, structure-activity relationship (SAR) studies of COXIBs showed that a COX-2 selectivity raised due to a hydrophobic interaction with an extra hydrophobic region and polar interactions with a secondary polar pocket that are found in COX-2 isozyme [18]. Moreover, the presence of electron withdrawing group in one of the aryl substitutions in the para position is more preferable than corresponding electron donating group [18]. Various previous studies were implemented to synthesize selective COX-2 inhibitors by using different methods [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the presence of electron withdrawing group in one of the aryl substitutions in the para position is more preferable than corresponding electron donating group [18]. Various previous studies were implemented to synthesize selective COX-2 inhibitors by using different methods [18][19][20][21][22]. e reported syntheses are commonly complex which makes the production costs more expensive and beyond the reach of an ordinary person.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

Assali

Abualhasan

Sawaftah

et al. 2020

Journal of Chemistry

View full text Add to dashboard Cite

Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. ese series of derivatives were synthesized by different reactions like Vilsmeier-Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC 50 values in 0.551-0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC 50 � 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC 50 � 0.098 μM, SI � 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all synthesized compounds including the reference celecoxib with IC 50 � 0.002 μM and SI � 162.5 as it could better fit the extra hydrophobic pocket which is present in the COX-2 enzyme. Moreover, the docking study supports the obtained SAR data and binding similarities and differences on both isozymes.

show abstract

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

Cited by 56 publications

References 61 publications

Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

Differences in the profile of cytokine expression induced by implantation of oncogenic and non-oncogenic millipore filters

Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

Contact Info

Product

Resources

About