Discovery and structure–activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers

Tai, Vincent W.‐F.; Sperandio, David; Shelton, Emma; Litvak, Joane; Pararajasingham, Keith; Cebon, Ben; Lohman, Julia; Eksterowicz, John; Kantak, Seema S.; Sabbatini, Peter; Brown, Cindy; Zeitz, Jennifer; Reed, Chris; Maske, Bill; Graupe, Doris; Estevez, Alberto; Oeh, Jason; Wong, D.; Ni, Yicheng; Sprengeler, Paul A.; Yee, Robert M.; Magill, Catherine; Neri, Anthony; Cai, Sui Xiong; Drewe, John; Qiu, Ling; Herich, John; Tseng, Ben; Kasibhatla, Shailaja; Spencer, Jeffrey R.

doi:10.1016/j.bmcl.2006.06.018

Cited by 13 publications

(6 citation statements)

References 13 publications

(4 reference statements)

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“…While exploring derivatives of 2 , we found that 2-phenyl-oxazole-4-carboxamide derivative 3 was also active against M. tuberculosis . 2-Phenyl-oxazole-4-carboxamides are known inhibitors of histone deacetylase,14 Stat3,15 phosphodiesterase,16 phosphatase,17 thromboxane synthase,18 and kinase proteins,19 and known activators of cellular caspase activity 20. We synthesized derivatives of 3 to identify a more potent anti-tuberculosis agent 13.…”

Section: Introductionmentioning

confidence: 99%

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

et al. 2010

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A series of N- ((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides was synthesized by coppercatalyzed azide-alkyne cycloaddition (CuAAC) and afforded inhibitors of cancer cell growth. For example, compound 13e had an IC 50 of 46 nM against MCF-7 human breast tumor cells. Structure-activity relationship (SAR) studies demonstrated that (i) meta-phenoxy substitution of the N-1-benzyl group is important for antiproliferative activity and (ii) a variety of heterocyclic substitutions for the aryl group of the arylamide are tolerated. In silico COMPARE analysis of antiproliferative activity against the NCI-60 human tumor cell line panel revealed a correlation to clinically useful antimicrotubule agents such as paclitaxel and vincristine. This in silico correlation was supported by (i) in vitro inhibition of tubulin polymerization, (ii) G 2 /M-phase arrest in HeLa cells as assessed by flow cytometry, and (iii) perturbation of normal microtubule activity in HeLa cells as observed by confocal microscopy. The results demonstrate that N- ((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide is a readily accessible small molecule scaffold for compounds that inhibit tubulin polymerization and tumor cell growth.

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Section: Introductionmentioning

confidence: 99%

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

et al. 2010

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“…Compound 1541 and its analogues (Figure ) were the first in this class (Wolan, Zorn, Gray, & Wells, ). Additional caspase‐3 activators have also been introduced with a subtle difference in pharmacophoric groups and SAR (Aliabadi et al, ; Cai, Kasibhatla, Drewe, Reddy, & Zhang, ; Tai et al, ; Zhang, Drewe, Tseng, Kasibhatla, & Cai, ; Zhang et al, ; Zhang, Kasibhatla, et al, ) (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Anticancer activity of newly synthesized 1,1‐disubstituted cyclohexane‐1‐carboxamides: in vitro caspases mediated apoptosis activators in human cancer cell lines and their molecular modeling

Abd‐Allah

Salman

Saad

2019

Drug Development Research

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Novel 1,1‐disubstituted cyclohexane‐1‐carboxamides 6a‐h, 7a‐e, and 8a‐b were designed and synthesized as apoptotic inducers. Cytotoxicity test revealed that some compounds have strong to moderate effect, while others displayed weak action against different cancer cell lines including, MCF‐7, HepG2, A549, and HTC‐116. A549 carcinoma cell line exhibited higher sensitivity toward all synthesized candidates especially compounds 6a and 8a which offered the lowest IC50 values 3.03 and 5.21 μM, respectively, relative to the positive control doxorubicin with IC50 value of 3.01 μM. Compared to doxorubicin treatment, compounds 6a and 8a induced caspases‐3, ‐8, and ‐9 activities and G2/M growth arrest in A549 carcinoma cell line. The expression levels of p53 (tumor suppressor protein that in humans is encoded by the TP53 gene), Bax (apoptosis regulator protein in humans that is encoded by bax gene), and the Bax/Bcl‐2 ratio were all higher than those in doxorubicin‐treated cells (Bcl‐2, B‐cell lymphoma 2, encoded in humans by the Bcl‐2 gene). Additionally, compounds 6a and 8a appeared to exhibit higher selectivity against MCF‐10 human breast normal cell line. The synthesized congeners could be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways. Moreover, compound 6a was able to form complex with zinc ions as indicated by UV spectrophotometry which revealed its ability for being caspase activator. Molecular docking studies expected the interactions and binding modes of the synthesized inhibitors in the caspase‐3 active site.

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“…Recently, 2,4‐disubstituted oxazoles derivatives have been reported to have pronounced anti‐tumor activities by triggering apoptosis in human tumor cells .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

El‐Nezhawy

Eweas

Radwan

et al. 2015

Journal of Heterocyclic Chem

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Discovery and structure–activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers

Cited by 13 publications

References 13 publications

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

Anticancer activity of newly synthesized 1,1‐disubstituted cyclohexane‐1‐carboxamides: in vitro caspases mediated apoptosis activators in human cancer cell lines and their molecular modeling

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

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