Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

Farag, Ahmed Karam; Hassan, Ahmed H.E.; Chung, Kyung‐Sook; Lee, Jeonghun; Gil, Hyo-Sun; Lee, Kyung‐Tae; Roh, Eun Joo

doi:10.1016/j.bioorg.2020.104121

Cited by 24 publications

(15 citation statements)

References 70 publications

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“…Given that apoptosis inhibits cancer cell growth with minimal effects on normal cells, compounds that induce apoptosis might thus have potential utility in cancer treatment [ 39 ]. In a previous study, we found that AKF-D52 showed growth-inhibitory and cytotoxic effects on multiple cancer cell lines, including lung, colorectal, skin, ovarian, renal, prostate, breast, and hematologic cancers [ 26 ]. In the present study, we investigated the mechanisms underlying the antiproliferative effects of AKF-D52 at the molecular level, both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…AKF-D52 ( Figure 1 A) was prepared as previously described [ 26 ]. Fetal bovine serum (FBS), penicillin/streptomycin (PS), Minimum Essential Medium (MEM), and RPMI 1640 medium were obtained from Life Technologies Inc (Chicago, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, we found that a novel phenoxypyrimidine urea derivative, 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a diarylurea-2,4-disubstituted pyrimidine hybrid compound, showed antiproliferative properties in various cancer cells and inhibitory effect on multiple kinases, especially inhibition against Feline McDonough Sarcoma (FMS) and c-KIT. However, as the inhibition of the AKF-D52 on these protein tyrosine kinases is lower relative to sorafenib and pazopanib, it might only help to explain the evoked antiproliferative activity partially [ 26 ]. Notably, AKF-D52 induced apoptotic cell death in A549 lung cancer cells, but the molecular mechanisms underlying the growth inhibitory efficacy of AKF-D52 in human NSCLC cells have yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

Gil

Lee

Farag³

et al. 2021

Cancers

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Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

Gil

Lee

Farag³

et al. 2021

Cancers

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“…Repurposing, reprofiling, repositioning, or redirecting are closely correlated terms that have been coined to describe the attempt to deploy compound(s) for targeting a certain pathological condition(s) although originally they are/were used; developed to be used or failed the process of development to be used for another disease(s) [6][7][8][9][10] . Although such a strategy towards drug discovery and development was previously known, implemented, and indeed, resulted in successful discoveries, the current global threats because of pandemic COVID-19 increased the awareness and sparked more interest in this strategy.…”

Section: Introductionmentioning

confidence: 99%

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani

Hassan

Phan

Yoon

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH 2 O- and the N- acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC 50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

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“…[1] Nowadays, there have been many successful cases of obtaining active molecules via molecular hybridization strategy. [2][3][4][5][6][7] Thiazole matrices play a prominent role in drug design, [8][9][10] as they feature high flexibility in location of substituents, i. e. substituents can be introduced at positions C-2, C-4 and, C-5. Moreover, by virtue of prominent bioactivities of various thiazole derivatives, thiazole ring has drawn tremendous attention in agrochemistry.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Fungicidal Activity of Novel 2‐aryl‐thiazole Derivatives Containing Saccharin Motif

et al. 2020

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A series of novel 2-aryl-thiazole derivatives containing saccharin were designed and synthesized by a facile method, and their structures were characterized by 1 H NMR, 13 C NMR and HMRS. Biological tests indicated that the parts of 2-aryl-thiazole derivatives possess potent fungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, and Alternaria altanata. Especially, N-((2-(4-chlorophenyl)thiazol-4-yl)methyl)-4-(1,1-dioxido-3-oxobenzo[d]isothia-zol-2(3H)-yl)butanamide (7 p) displays inhibition rates of 49.2 % and 41.9 % at a concentration of 10 mg/L against S. sclerotiorum and B. cinerea respectively, while 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-N-((2-(4methoxyphenyl)thiazol-4-yl)methyl)acetamide (7 f) shows an inhibition rate of 53.3 % at a concentration of 10 mg/L against A. altanata. Furthermore, the structure-activity relationship was discussed. It suggested that the 2-aryl-thiazole group can be considered as a precursor structure for further design of fungicides.

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Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

Cited by 24 publications

References 70 publications

AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani

Design, Synthesis and Fungicidal Activity of Novel 2‐aryl‐thiazole Derivatives Containing Saccharin Motif

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