Design, synthesis and biological evaluation of novel α-aminophosphonate oxadiazoles via optimized iron triflate catalyzed reaction as apoptotic inducers

Ewies, Ewies F.; El‐Hussieny, Marwa; El‐Sayed, Naglaa F.; Fouad, Marwa A.

doi:10.1016/j.ejmech.2019.07.029

Cited by 31 publications

(18 citation statements)

References 75 publications

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“…Accordingly, and in continuation of our ongoing research (Boulos et al, 2013a;El-Sayed et al, 2016;Ewies et al, 2014;Ewies et al, 2015;Ewies et al, 2016a;Ewies et al, 2016b;Ewies et al, 2019;Ibrahim et al, 2015, El-Husseiny et al, 2020El-Sayed et al, 2020) toward obtaining new compounds as promising biological activities and based on F I G U R E 2 Design of target compounds 5a-j, 6a,b, 7a-e, and 8a-f the previously reported findings regarding the biological activity of benzofuran and indole nucleus, we focused our attention on exploring the possibility of replacement of the 3,4,5-trimethoxybenzoyl moiety at position 2 of compound IV with a fluoro or trifluoromethyl substituted phenyl diazinyl moiety as in compounds 5a-j, 6a,b, and 8a-f. Both fluorine substituent or trifluoromethyl group are known to induce high effect on the binding affinity and increase stability of cell membrane as well as its permeability against metabolic oxidation (Usachev et al, 2008;Usachev et al, 2012).…”

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confidence: 61%

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

El‐Sayed

El‐Hussieny

Ewies

et al. 2021

Drug Development Research

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Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2‐Acetylbenzofuran derivatives 1a,b and 3‐acetylindole 1c were condensed with Wittig reagents 2a–d and Wittig‐Horner reagents 3a–e to afford the respective 2‐ethylidene derivatives 5a–j and 7a–e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran‐2‐ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a–c to give 1:1 adduct for which the Oxaphospholo[4,3‐b]benzofuran‐7‐yl)diazene derivatives 8a–f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

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confidence: 61%

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

El‐Sayed

El‐Hussieny

Ewies

et al. 2021

Drug Development Research

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“…Tumor cells are characterized by, e.g., an unlimited potential for proliferation [ 26 ]; hence, restriction of tumor cell proliferation via cell cycle arrest and/or apoptosis induction is an expected feature of new compounds with anti-cancer potential. It is reported that OP compounds, including those based on α-aminophosphonate scaffolds, exhibit anti-proliferative activity towards various types of cancer, e.g., leukemia, melanoma, colon cancer, hepatoma, breast cancer, lung cancer, and neuroblastoma [ 3 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. According to these reports, the growth inhibitory effect of αAPs was associated with apoptosis induction and cell cycle arrest mostly at the G 2 phase.…”

Section: Discussionmentioning

confidence: 99%

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity

Mizerska-Kowalska

Sowa

Donarska

et al. 2022

IJMS

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Many organophosphorus compounds (OPs), especially various α-aminophosphonates, exhibit anti-cancer activities. They act, among others, as inhibitors of the proteases implicated in cancerogenesis. Thesetypes of inhibitors weredescribed, e.g., for neutral endopeptidase (NEP) expressed in different cancer cells, including osteosarcoma (OS). The aim of the present study isto evaluate new borane-protected derivatives of phosphonous acid (compounds 1–7) in terms of their drug-likeness properties, anti-osteosarcoma activities in vitro (against HOS and Saos-2 cells), and use as potential NEP inhibitors. The results revealed that all tested compounds exhibited the physicochemical and ADME properties typical for small-molecule drugs. However, compound 4 did not show capability of blood–brain barrier penetration (Lipiński and Veber rules;SwissAdme tool). Moreover, the α-aminophosphonite-boranes (compounds 4–7) exhibited stronger anti-proliferative activity against OS cells than the other phosphonous acid-borane derivatives (compounds 1–3),especially regarding HOS cells (MTT assay). The most promising compounds 4 and 6 induced apoptosis through the activation of caspase 3 and/or cell cycle arrest at the G2 phase (flow cytometry). Compound 4 inhibited the migration and invasiveness of highly aggressive HOS cells (wound/transwell and BME-coated transwell assays, respectively). Additionally, compound 4 and, to a lesser extent, compound 6 inhibited NEP activity (fluorometric assay). This activity of compound 4 was involved in its anti-proliferative potential (BrdU assay). The present study shows that compound 4 can be considered a potential anti-osteosarcoma agent and a scaffold for the development of new NEP inhibitors.

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“…Zinc triflate and iron triflate also proved to be efficient catalysts in the three-component condensation when different substituted amines or an oxadiazole-related acid hydrazide ( 14 ) were reacted with benzaldehyde and diethyl phosphite. These reactions took place under mild conditions, mostly in good yields ( Scheme 7 and Scheme 8 ) [ 30 , 31 ].…”

Section: Kabachnik–fields Reactions With Dialkyl Phosphites Alkyl H -Phosphinates and Secondary Phosphine Oxidesmentioning

confidence: 99%

Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction

Varga

Keglevich

2021

Molecules

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The Kabachnik–Fields reaction, comprising the condensation of an amine, oxo compound and a P-reagent (generally a >P(O)H species or trialkyl phosphite), still attracts interest due to the challenging synthetic procedures and the potential biological activity of the resulting α-aminophosphonic derivatives. Following the success of the first part (Molecules 2012, 17, 12821), here we summarize the synthetic developments in this field accumulated in the last decade. The procedures compiled include catalytic accomplishments as well as catalyst-free and/or solvent-free “greener” protocols. The products embrace α-aminophosphonates, α-aminophosphinates, and α-aminophosphine oxides along with different bis derivatives from the double phospha-Mannich approach. The newer developments of the aza-Pudovik reactions are also included.

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Design, synthesis and biological evaluation of novel α-aminophosphonate oxadiazoles via optimized iron triflate catalyzed reaction as apoptotic inducers

Cited by 31 publications

References 75 publications

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity

Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction

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