Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates

Abdou, Wafaa M.; Barghash, Reham F.; Khidre, Rizk E.

doi:10.1007/s00706-013-0950-6

Cited by 25 publications

(16 citation statements)

References 18 publications

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“…Generally, cancers of the breast, lung, colon, and prostate are the most frequent types of cancer worldwide [1][2][3]. This paper along with our recent efforts focuses on developing, identifying, and optimizing new entities of anticancer properties [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation, and SAR studies

2015

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New and efficient conjugate addition reaction of trimethyl, triethyl, and triisopropyl phosphites with 2-azido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was developed and furnished spiro-triazaphosphole-oxide derivatives in &70 % yield. Contrary to these results, linear substituted phosphoramidates were obtained from the reaction of the azide with dimethyl, diethyl, and diisopropyl phosphites.N-Alkylaminoor 2-aminotetrahydrobenzo[b]thiophene-3-carbonitrile was also isolated in *10 % yield from the previous two reactions. In the context of this work, hexaalkylphosphorus triamides were caused to react with the same substrate afforded the corresponding phosphoric triamides only in the presence of a protonating agent (dil. alcohol). The three reactions proceeded smoothly, cleanly, and were completed within *6 h at r.t. Pharmacological evaluation results of antibreast, anticolon, and antiprostate carcinoma cell lines properties for the products were discussed in terms of structure-activity relationship to define a chromophore for lead compounds. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation, and SAR studies

2015

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“…Many isoxazole-containing heterocycles have diverse biological activity, including antimicrobial, fungicidal, anticonvulsant, HDAC inhibitory, protein-tyrosine phosphatase 1B (PTP1B) inhibitory, analgesic, antioxidant, anti-apoptotic, anti-obesity, COX-2 inhibitory, nematicidal, anti-nociceptive, anti-inflammatory, antiviral, anti-tubercular, herbicidal, protein kinase C (PKC) inhibitory, and antineoplastic [101][102][103][104][105][106][107] activity. The isoxazole nucleus is also found in inhibitory agents [108], sulfisoxazoles [109], antibiotics [110,111], and anti-androgens [112,113].…”

Section: Introductionmentioning

confidence: 99%

Efficient tandem synthesis of a variety of pyran-annulated heterocycles, 3,4-disubstituted isoxazol-5(4H)-ones, and α,β-unsaturated nitriles catalyzed by potassium hydrogen phthalate in water

Kiyani

Ghorbani

2014

Res Chem Intermed

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A variety of 4H-chromenes, benzochromenes, 4,5-dihydropyrano[3,2-c]chromenes, 4H-pyran-3-carboxylates, and 3,4-disubstituted isoxazol-5(4H)-ones have been synthesized in high yields by using potassium hydrogen phthalate (KHP) as an inexpensive, commercially available catalyst. It was found that the threecomponent tandem reaction enabled synthesis of pyran-annulated heterocycles in water at 50°C. 3,4-Disubstituted isoxazol-5(4H)-ones were synthesized by use of 10 mol% KHP in water at room temperature. Also, treatment of methylene-containing compounds (malononitrile or ethyl cyanoacetate) with aromatic aldehydes in the presence of 5 mol% KHP resulted in a,b-unsaturated nitriles. The procedure is an easily performed, straightforward method for synthesis of a variety of pyranannulated compounds, isoxazol-5(4H)-one-containing heterocycles, and Knoevenagel adducts. The reaction is safe, uses mild conditions, and is environmentally benign. Other notable advantages are reuse of the catalyst, no use of hazardous organic solvents, and ease of work-up.

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“…It was interesting to observe that applying a similar reaction to equivalent amounts of isothiocyanate 1 with unsaturated phosphoryl carbanions: diethyl vinylphosphonate (4) or methylallyl analog (6) …”

Section: Resultsmentioning

confidence: 99%

“…Drugs, most frequently cross the biological barriers through passive transport, which strongly depends on their lipophilicity. Therefore, hydrophobicity is one of the most important physical properties of biologically active compounds.Our previous studies [5,6] as well as others [19,20] showed that introduction of a tertiary butyl group increases the lipophilicity of the molecule, which is always associated with its pharmacological properties.In sequel, we measured the hydrophobicity of the synthesized phosphonates 3a-3i, 5, and 7 as a tool for predication to bioscreening activity. The determined log K were compared with the calculated (log P / Clog P values) using two commercially available programs.…”

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“…Furthermore, almost all of the chemotherapy drugs currently on the market cause serious side effects [4]. Based on these facts, designing of new chemical entities as anticancer agents requires the simulation of a suitable bioactive pharmacophore.In a recent series of papers [5][6][7], we reported the synthesis of 5,7-di-tert-butylbenzoxazoles substituted in the C(2) position with phosphor ester derivatives and the evaluation of their pharmacological properties, especially their cytotoxicity growth inhibition of 50% (GI 50 mg/L) properties. Many of these compounds exhibited moderate to excellent effects against different carcinoma cell lines.…”

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Synthesis of Lipophilic‐2‐Mercaptobenzoxazoles and 2‐Spirothiophene‐Phosphonate Derivatives as Potent Anticancer Agents

Abdou

Barghash

Bekheit

2016

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).In honor and in memory of Emeritus Professor Richard Neidlein.As a part of our ongoing research program in developing new anticancer agents, herein, we report the synthesis of a series of 2-mercapto-2,3-dihydrobenzoxazole-2-methyl-, -2-thioethyl-, and/or 2-spirothiophenephosphonates. Five of these new compounds that combine three bioactive moieties: oxazole, thiol, and phosphonate motifs, exhibited remarkable growth inhibition against 13 carcinoma cell lines. The results of the experimentally determined log K and clog P values are in agreement with Lipinski Rule >5 and showed a strong correlation with the pharmacological results; nevertheless, it is poorly consisted with calculated log P/Clog P and log P/ACD. J. Heterocyclic Chem., 000, 00 (2016). INTRODUCTIONCancer disease is initiated by a series of cumulative genetic and epigenetic changes that occur in normal cells and characterized by a number of consecutive abnormal behaviors [1,2]. Taking into account the rising trend of cancer incidences in various organs, effective therapies are urgently needed to control human malignancies. Although a variety of anticancer drugs are currently in clinical use, and can be applied successfully for a treatment of several neoplastic diseases, the response of solid tumors to available anticancer chemotherapy has been poor [3]. Furthermore, almost all of the chemotherapy drugs currently on the market cause serious side effects [4]. Based on these facts, designing of new chemical entities as anticancer agents requires the simulation of a suitable bioactive pharmacophore.In a recent series of papers [5][6][7], we reported the synthesis of 5,7-di-tert-butylbenzoxazoles substituted in the C(2) position with phosphor ester derivatives and the evaluation of their pharmacological properties, especially their cytotoxicity growth inhibition of 50% (GI 50 mg/L) properties. Many of these compounds exhibited moderate to excellent effects against different carcinoma cell lines. It is claimed that the advantage of these compounds is the fact that they possess high lipophilicity, which is considered a useful predictive parameter in the bioactivity. As a follow-up, and in continuing of our running research program [6][7][8][9][10][11], herein, we investigated a microwave-assisted synthesis of new series of 5,7-di-tert-butylbenzoxazoles possess in the C(2) position a mercapto-, thioethyl-, and/or spirothiophene-phosphonates. We presumed that these compounds may have superior antineoplastic potency because of their high hydrophobicity and the incorporation of a thiol-phosphonate-and/or thioether motifs. Sulfur containing organic compounds are extensively useful as anticancer agents [12]. RESULTS AND DISCUSSIONSynthetic pathways depicted in Schemes 1 and 2 outlined the chemistry of applying a variety of Wadsworth-Horner-Emmons reagents to 2,4-di-tert-butyl-6-isothiocyanatophenol. The required isothiocyanate 1 was prepared for the first time according to Wong and Dolman method [13] from its parent ...

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Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates

Cited by 25 publications

References 18 publications

Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation, and SAR studies

Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation, and SAR studies

Efficient tandem synthesis of a variety of pyran-annulated heterocycles, 3,4-disubstituted isoxazol-5(4H)-ones, and α,β-unsaturated nitriles catalyzed by potassium hydrogen phthalate in water

Synthesis of Lipophilic‐2‐Mercaptobenzoxazoles and 2‐Spirothiophene‐Phosphonate Derivatives as Potent Anticancer Agents

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