Cage Dimeric 4-Aryl-1,4-dihydropyridines as Promising Lead Structures for the Development of a Novel Class of HIV-1 Protease Inhibitors

Hilgeroth, Andreas; Billich, Andreas

doi:10.1002/(sici)1521-4184(19991)332:1<3::aid-ardp3>3.0.co;2-1

Cited by 17 publications

(7 citation statements)

References 8 publications

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“…The structure of 6,12-diaryl-3,9-diazatetraasterane-1,5,7,11-tetracarboxylates ( Figure 1 ) has been synthesized as a therapeutic agent for inhibiting the activity of the HIV-1 protease [ 1 , 2 ]. However, the antitumor effect of 3,9-diazatetraasterane(DDTC) on cancer and the underlying mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 99%

6,12-Diphenyl-3, 9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate Inhibits Proliferation, Migration and Promotes Apoptosis in Ovarian Cancer Cells

Chen

Wang

et al. 2020

Disease Markers

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6,12-Diphenyl-3,9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate (DDTC) has been synthesized by the photodimerization of 4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate. The potential of theercvantitumor activity and mechanism were investigated in vitro using MTT assay in human lung cancer cell line A549, ovarian cancer cell lines SKOV3 and A2780, breast cancer cell line MCF-7, gastric cancer cell line BGC-823, colon cancer cell line HT29, prostate cancer cell line DU145, and liver cancer cell line SMMC7721. The results show that DDTC can inhibit the growth of ovarian cancer SKOV3 and A2780 cells. The best IC50 value is approximately 5.29±0.38 and 4.29±0.39 μM, respectively. DDTC induced the cell cycle arrest in the G2 phase by flow cytometric analysis. The migration and invasion of ovarian cancer SKOV3 and A2780 cells were inhibited by DDTC. DDTC could increase the expression protein level of E-cadherin in A2780 cells and ascend the expression protein and mRNA levels of E-cadherin in SKOV3 cells. DDTC could also decrease the protein and mRNA expression of EMT (epithelial-to-mesenchymal transition) markers of N-cadherin and Vimentin. mRNA and protein expression level of checkpoint kinase 1 (Chk1) were significantly increased and expressions of cyclin-dependent kinase (CDK1) and cell division cycle 25a (Cdc25a) were decreased in the SKOV3 and A2780 cell lines. Moreover, DDTC induced apoptosis by the cleavage and activation of caspase 3 and caspase 9.

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Section: Introductionmentioning

confidence: 99%

6,12-Diphenyl-3, 9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate Inhibits Proliferation, Migration and Promotes Apoptosis in Ovarian Cancer Cells

Chen

Wang

et al. 2020

Disease Markers

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“…Hilgeroth and co‐workers have reported N‐substituted cage dimeric 4‐aryl‐1,4‐dihydropyridines as a novel class of HIV‐1 protease inhibitors in 1999. The compounds they investigated exerted 6 – 32% inhibition at 25 and 50 μ m on the activity of HIV‐1 protease . In another work, the same researchers prepared a series of novel N–H and N‐alkyl‐substituted cage dimeric 4‐aryl‐1,4‐dihydropyridines.…”

Section: Introductionmentioning

confidence: 99%

“…The compounds they investigated exerted 6 -32% inhibition at 25 and 50 lM on the activity of HIV-1 protease. [16] In another work, the same researchers prepared a series of novel N-H and N-alkyl-substituted cage dimeric 4-aryl-1,4dihydropyridines. As HIV-1 protease inhibitors, their IC 50 values were between 16.1 and 262 lM.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4‐[4‐Arylpyridin‐1(4H)‐yl]benzoic Acid Derivatives as Anti‐HIV‐1 Agents

Sepehri

Soleymani

Zabihollahi

et al. 2017

Chemistry & Biodiversity

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The structural similarities between N1 substituted 1,4-dihydropyridines and the known gp41 inhibitors, NB-2 and NB-64, were considered in the current research for the design of some novel anti-HIV-1 agents. A series of novel 4-[4-arylpyridin-1(4H)-yl]benzoic acid derivatives were synthesized and after a comprehensive structural elucidation were screened for in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate to good inhibitory activity against HIV-1 growth and were evaluated for in vitro cytotoxic activity using XTT assay at the concentration of 100 μm. Among the tested compounds, 1c, 1d and 1e showed potent anti-HIV-1 activity against P24 expression at 100 μm with inhibition percentage of 84.00%, 76.42% and 80.50%, respectively. All the studied compounds possessed no significant cytotoxicity on MT-2 cell line. The binding modes of these compounds to gp41 binding site were determined through molecular docking study. Docking studies proved 1a as the most potent compound and binding maps exhibited that the activities might be attributed to the electrostatic and hydrophobic interactions and additional H-bonds with the gp41 binding site. The Lipinski's 'rule of five' and drug-likeness criteria were also calculated for the studied compounds. All derivatives obeyed the Lipinski's 'rule of five' and had drug-like features. The findings of this study suggest that novel 4-[4-arylpyridin-1(4H)-yl]benzoic acid might be a promising scaffold for the discovery and development of novel anti-HIV-1 agents.

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“…6,7) Cage 3,9-diazatetraasterane have recently been developed as a novel class of non-peptidic PIs with moderate but promising activities of their first representatives. [8][9][10][11] With a hitherto unknown substituted tetraasterane-analogous drug skeleton, 3,9-dioxatetraasterane (1, tetraethyl 2,4,8,10-tetramethyl-6,12-diaryl-3,9-dioxapentacyclo[6.4.0.0 2,7 •0 4,11 •0 5,10 ] dodecane-1,5,7,11-tetracarboxylate) are synthesized by photocycloaddition of 4-aryl-4H-pyranes ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 3,9-Dioxatetraasteranes as <i>C</i><sub>2</sub>-Symmetric HIV-1 Protease Inhibitors and Docking Study

Wang

et al. 2019

Biological & Pharmaceutical Bulletin

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tetracarboxylates (simplified as 3,9-dioxatetraasteranes) with C 2-symmetric structural characteristics were synthesized through the [2 2] photocycloaddition of the diethyl 2,6-dimethyl-4-aryl-4Hpyran-3,5-dicarboxylates. Besides, their anti-human immunodeficiency virus (HIV)-1 activities were evaluated by enzyme-linked immunosorbent assay (ELISA) assay against HIV-1 (IIIB) replication in MT-4 cell culture. The result showed that the tested compounds exhibited potential activates with IC 50 values less than 110 nM. Furthermore, docking study was carried out to study the binding mode of these compounds. The results indicated that the overall orientation of the inhibitors in the active site were similar to that of the cyclic urea AHA001 and a hydrogen bond with the protein residues might play a crucial role in their anti-HIV-1 activities. Such results will provide a theoretical foundation for further investigations on the biological activity of 3,9-dioxatetraasteranes.

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Cage Dimeric 4-Aryl-1,4-dihydropyridines as Promising Lead Structures for the Development of a Novel Class of HIV-1 Protease Inhibitors

Cited by 17 publications

References 8 publications

6,12-Diphenyl-3, 9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate Inhibits Proliferation, Migration and Promotes Apoptosis in Ovarian Cancer Cells

6,12-Diphenyl-3, 9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate Inhibits Proliferation, Migration and Promotes Apoptosis in Ovarian Cancer Cells

Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4‐[4‐Arylpyridin‐1(4H)‐yl]benzoic Acid Derivatives as Anti‐HIV‐1 Agents

Synthesis and Biological Evaluation of 3,9-Dioxatetraasteranes as <i>C</i><sub>2</sub>-Symmetric HIV-1 Protease Inhibitors and Docking Study

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