Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2′(1′H)-pyrrolo[3,4-c]pyrrole]-2,3′,5′(1H,2′aH,4′H)-triones

Girgis, Adel S.; Stawiński, Jacek; Ismail, Nasser S. M.; Farag, Hanaa

doi:10.1016/j.ejmech.2011.10.058

Cited by 104 publications

(65 citation statements)

References 60 publications

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“…Compound 4g was the most effective one with IC 50 =0.00586 mM compared with Doxorubicin (IC 50 =0.00686 mM). This derivative was selected by US-NCI for more antitumor activity screening [30][31][32][33][34][35] The observed data expressed as GI 50 (the concentration resulting in a 50% growth inhibition of the tumor compared with the control experiments), TGI (the concentration resulting in a 100% growth inhibition of the tumor compared with the control experiments) and LC 50 were presented in Table 2. It showed promising activity against 38 cell lines especially, HOP-92, NCI-H226 (non-small cell lung cancer), GI 50 =0.000865, 0.00127 mM, respectively, SF-539, SNB-75 (CNS cancer), GI 50 =0.00144, 0.000811 mM, respectively, MALME-3M, SK-MEL-5 (melanoma), GI 50 =0.0016, 0.0015 mM, respectively, OVCAR-4, SK-OV-3 (ovarian cancer), GI 50 =0.00102, 0.00115 mM, respectively, 786-0, A498, RXF 393, UO-31 (renal cancer), GI 50 =0.00112, 0.00111, 0.00118, 0.00148 mM, respectively and MDA-MB-231/ATCC, HS 578T (breast cancer), GI 50 =0.00133, 0.00113 mM, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…multiple linear regression modeling (MLR). 15,35,39) Equation 1 shows our best-performing QSAR model (Fig. 5 exhibits the corresponding scatter plots of experimental versus estimated bioactivity values for the ) and residuals between the predicted and experimental activity of the training set (Table 5).…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacophores explain the variability of bioactivity with respect to the geometric localization of the chemical features present in the molecules. 15,35) Twenty nine compounds (4a-f, 4h-j, 5a, b, 5d-h and the previously prepared Ia-j and IIIa-c 15) ) were taken as a training set and the remaining two compounds, 4g (with potent antitumor activity) and 5c (with mild activity) were used as a test set. The observed HYPOGEN identifies a 3D array of a maximum of three chemical features common to the training set that provide relative alignment for each input molecule, consistent with its binding mode to a proposed common receptor site.…”

Section: Resultsmentioning

confidence: 99%

“…15,[35][36][37][38] Thus, a classical QSAR analysis was employed to search for the best combination of orthogonal pharmacophores using a fit value and other structural descriptors (connectivity, topological, etc.) capable of explaining bioactivity variation across a collected list of the descriptors, allowing different pharmacophoric models competing within the 3D-QSAR framework.…”

Section: Resultsmentioning

confidence: 99%

“…Antitumor Activity In-vitro antitumor activity of the tested compounds was screened utilizing Sulfo-Rodamine B (SRB) standard method 15,[29][30][31][32][33][34][35] in the National Cancer Institute, Cairo University, Egypt. All the prepared target compounds (4a-j, 5a-h) were tested for their antitumor properties against HCT116 "colon" and T47D "breast" cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

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Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Hanna

George

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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2-(5-Arylidene-4-oxo-3-phenyl-thiazolidin-2-ylidene)-3-oxo-propionitriles 4a-j were prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a, b. The latter was obtained via electrophilic attack of phenylisothiocyanate on 3-oxo-propionitriles 1a, b followed by reaction with chloroacetyl chloride under basic condition. Additionally, 2-(5-heteroalicyclic methylene) analogues 5a-h were prepared via Mannich reaction of the appropriate secondary amines and formaldehyde with 4-thiazolidinones 3a, b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116 and breast T47D cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explain the observed antitumor properties.Key words thiazolidinone; quantitative structure-activity relationship; antitumor activity; 3-oxo-propionitrile; HCT116; T47D Cancer ranks second in diseases leading to mortality, following only cardiovascular diseases. One-quarter of all deaths in the United States are caused by cancer.1) Out of the many cancer diseases, breast cancer is the most prevalent cancer in women and represents the second highest leading cause of cancer death in this population after lung cancer.2) Colorectal cancer is the third most common cancer in both men and women, 91% of cases are diagnosed in individuals 50 years of age and older. 1) Chemotherapy is widely used to treat and control cell growth and limit the spread of cancer cells to other sites. Although, there is a success with certain forms of cancer, drug therapy has only limited impact against the three major killers: carcinoma of lung, breast and colorectal system. Therefore, there is a need to develop novel antitumor agents to treat and combat this disease.Several promising antitumor agents containing thiazolidine and thiazolidinone scaffolds have been identified to have a broad range of anticancer activities.3-14) Previously, we reported promising antitumor properties of a variety of 5-arylidene thiazolidinone derivatives Ia-c (Fig. 1) exhibiting considerable cytotoxic activity against colon HCT116 cancer cell lines compared with Doxorubicin (reference standard, IC 50 =0.00686 mM).15) In continuation of these previous findings and in order to optimize novel antitumor active agents possessing the same thiazolidinone core, it is intended in the present work to perform some modifications in the adopted structures via inserting heteroalicyclic amines (morpholinyl or piperidinyl functions, 4a-j) instead of the aromatic amines Ia-c due to their hydrophilic properties. Moreover, a series of heteroalicyclic methylene containing compounds 5a-h will be also prepared replacing the arylidene moiety of Ia-c (Fig. 1). Additionally, many morpholine and piperidine containing compounds were known as anticancer active agents that exerted their actions via inhibition of different targets such as phosphatidylinositol 3-kinases (PI3Ks) and histone deacetylase (HDAC). [16][17][18][19][20] Moreover, the piperidine deriva...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Hanna

George

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Diastereo‐ and Enantioselective Synthesis of Chiral Pyrrolidine‐Fused Spirooxindoles via Organocatalytic [3+2] 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Maleimides

Zhao

Meng

et al. 2015

Adv Synth Catal

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In the presence of a Cinchona alkaloid‐based squaramide organocatalyst, the [3+2] cycloaddition of isatin‐derived azomethine ylides with maleimides proceeded readily, thus delivering the desired pyrrolidine‐fused spirooxindoles in 61–89% yields with >20:1 dr and 12 to >99 % ee. The absolute configuration of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione was unambiguously determined by means of X‐ray single crystal structure analysis. The reaction mechanism was hypothesized to account for the enantioselective formation of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione.magnified image

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Stereoselective Synthesis of CF₃‐Containing Spirooxindoles via 1,3‐Dipolar Cycloaddition by Dipeptide‐Based Phosphonium Salt Catalysis

Liu

et al. 2020

Adv Synth Catal

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Reported here is an alternative method for asymmetric synthesis of the CF3‐substituted 3,2′‐pyrrolidinyl spirooxindoles via 1,3‐dipolar cycloaddition by employing dipeptide‐based chiral phosphonium salt as a phase‐transfer catalyst. Under the optimal reaction conditions, a variety of CF3‐substituted 3,2′‐pyrrolidinyl spirooxindole derivatives were readily prepared in high yields as a single diastereomer with high enantiomeric access (>20:1 dr and up to 94% ee).

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Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2′(1′H)-pyrrolo[3,4-c]pyrrole]-2,3′,5′(1H,2′aH,4′H)-triones

Cited by 104 publications

References 60 publications

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Diastereo‐ and Enantioselective Synthesis of Chiral Pyrrolidine‐Fused Spirooxindoles via Organocatalytic [3+2] 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Maleimides

Stereoselective Synthesis of CF₃‐Containing Spirooxindoles via 1,3‐Dipolar Cycloaddition by Dipeptide‐Based Phosphonium Salt Catalysis

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Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2′(1′H)-pyrrolo[3,4-c]pyrrole]-2,3′,5′(1H,2′aH,4′H)-triones

Cited by 104 publications

References 60 publications

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Diastereo‐ and Enantioselective Synthesis of Chiral Pyrrolidine‐Fused Spirooxindoles via Organocatalytic [3+2] 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Maleimides

Stereoselective Synthesis of CF3‐Containing Spirooxindoles via 1,3‐Dipolar Cycloaddition by Dipeptide‐Based Phosphonium Salt Catalysis

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Stereoselective Synthesis of CF₃‐Containing Spirooxindoles via 1,3‐Dipolar Cycloaddition by Dipeptide‐Based Phosphonium Salt Catalysis