Carbohydrates U 0500 A Facile and Eco-Friendly Method for the Synthesis of 1,2-Orthoesters of Car... more Carbohydrates U 0500 A Facile and Eco-Friendly Method for the Synthesis of 1,2-Orthoesters of Carbohydrates in Ionic Liquid.-Orthoesters such as (III) are prepared by a novel method using perbenzoylated glycopyranosyl bromide in the presence of 2,6-lutidine in ionic liquid.-(RADHAKRISHNAN*,
With the aim of the synthesis of chemically modified cyclodextrins bearing polyamine pendant grou... more With the aim of the synthesis of chemically modified cyclodextrins bearing polyamine pendant groups, potentially useful as capping agents for the preparation of nanosized metal systems or as auxiliaries for gene transfection, the reaction between the heptakis-(6-iodo)-(6-deoxy)-β-cyclodextrin and various polyamines has been explored. This synthetic approach allows obtaining materials constituted by mixtures of cyclodextrins, having different degrees of substitution, which were satisfactorily characterized by means of various complementary techniques (ESI-MS, NMR, potentiometric titration). The products obtained were successfully subjected to preliminary tests for their binding abilities towards suitable organic guests and as capping agents for the preparation of stable silver nanoparticles.
In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized... more In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, 1H NMR, 13 C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G2 for liver sarcoma, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone (3), 1,2-naphthoquinone-2-semicarbazone (4), 4-amino-1,2-naphthoquinone 2-thiosemicarbazone (7) and 4-amino-1,2-naphthoquinone-2-semicarbazone (8) are active cytotoxic agents against different cancer cell lines with IC50 values in the range of 5.73–17.67 μM. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2-naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC50 values of all these compounds.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barb... more A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of a-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit a-glucosidase activity in a reversible mixed-type manner with IC 50 between 264.07 ± 1.87 and 448.63 ± 2.46 mM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of a-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a-k, 5, and 6 showed significant to moderate anti-glycation activity (IC 50 ¼ 31.5 ± 0.81 to 554.76 ± 9.1 mM).
A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzalde... more A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine was substituted by different amines (morpholine, piperidine, or diethylamine) to afford 2,4-dichloro-6-substituted-1,3,5-triazine. The second and third chlorines were substituted by benzaldehyde derivatives in the presence of Na2CO3 as a HCl scavenger to afford the target products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or microwave irradiation to afford the di-arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in less reaction time with good yield and pu...
Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against G... more Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg 10 −teixobactin as a reference, where the nonproteinogenic residue L-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity.
The first synthesis and biological activity of a teixobactin analogue is reported. Substitution o... more The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual l-allo-enduracididine residue by the naturally occurring l-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry.
www.cheminform.wiley-vch.de Enzyme inhibiting activity X 0220 Synthetic Reactions and Structural ... more www.cheminform.wiley-vch.de Enzyme inhibiting activity X 0220 Synthetic Reactions and Structural Studies of Heterocycles Containing Nitrogen Part. 19. Synthesis of Some Pyridazinylacetic Acid Derivatives as a Novel Class of Monoamine Oxidase-A Inhibitors.-All derivatives screened for their monoamine oxidase (MAO) activity are found to be more selective to the MAO-A isoform with compound (Ia) having the highest SI value.
In the course of comparing the effectiveness of several HOAt-and HOPfp-derived coupling reagents ... more In the course of comparing the effectiveness of several HOAt-and HOPfp-derived coupling reagents by cyclization and segment condensation of model sequences, using HPLC to follow the time course and to determine the outcome in terms of oligomerization and epimerization, we found a striking improvement of the less effective HOPfp-based coupling reagent (HPyOPfp), both with regard to reaction rate and extent of epimerization, when HOAt was added.
Although Fmoc amino acid fluorides are excellent reagents for coupling of moderately hindered ami... more Although Fmoc amino acid fluorides are excellent reagents for coupling of moderately hindered amino acids (e.g., Aib-to-Aib) they are not suited for significantly more hindered systems (e.g., Aib-to-MeAib). While urethane-protected acid chlorides are inherently more reactive than the fluorides they are also ineffective for hindered systems due to competing oxazolone formation. This limitation is bypassed if urethane protection is replaced by arenesulfonyl protection and the Aib-to-MeAib and even the MeAibto-MeAib couplings are easily achieved via the appropriate acid chlorides but not the acid fluorides.
Résumé/Abstract N, N, N′, N′-Tetramethylfluoroformamidiniumhexafluoro-phosphate (TFFH) has been s... more Résumé/Abstract N, N, N′, N′-Tetramethylfluoroformamidiniumhexafluoro-phosphate (TFFH) has been shown to be an excellentpeptide-coupling reagent. It is an easily handled, crystalline compound, it has a long shelf life, and it reacts rapidly with carboxylicacids to ...
Organic Preparations and Procedures International, 2004
Ring closure reactions Ring closure reactions O 0130 A Novel and Direct Method for the Preparatio... more Ring closure reactions Ring closure reactions O 0130 A Novel and Direct Method for the Preparation of 4-Amino-1,1,3,3-tetrasubstituted Guanidines and of [1,2,4]Triazolo-Fused Heterocyclic Derivatives.-The versatility of the chloroformamidinium salts (II) for the synthesis of guanidine derivatives (III) and of [1,2,4]triazolo-fused heterocycles like (V), (VII), and (IX) is demonstrated.-(ABDUL-GHANI, M.
Recent studies described the great impact of a non-benzotriazolic family of coupling reagents bas... more Recent studies described the great impact of a non-benzotriazolic family of coupling reagents based on ethyl 2-cyano-2-(hydroxyimino)acetate, Oxyma, as a powerful coupling methodology for peptide synthesis. Here we present the synthesis and evaluation of the derived phosphonium salts O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and tetrafluoroborate (PyOxB). Both coupling reagents exhibited higher capacity to suppress racemization in various peptide models and enhanced solubility in DMF and DCM than benzotriazole-based reagents. In addition, the hexafluorophosphate analog PyOxP, combined excellent stability with outstanding efficiency in the assembly of demanding penta and decapeptides that include consecutive Aib residues. Cyclization models revealed the advantages of PyOxP, which rendered a higher percentage of cyclic material than other known potent phosphonium salts.
OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbod... more OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbodiimide (DIC) approach for the synthesis of a novel series of α-ketoamide derivatives (4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino]benzoyl amino acid ester derivatives). OxymaPure showed clear superiority to HOBt/DIC or carbodiimide alone in terms of purity and yield. The title compounds were synthesized via the ring opening of N-acylisatin. First, N-acetylisatin was reacted with 4-aminobenzoic acid under
A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for re... more A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for reactivity in solution peptide synthesis. The new triazinyloxyimino derivatives failed to activate the carboxyl group during formation of peptide bonds, but gave the corresponding N-triazinyl amino acid derivatives as a major product. The oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) uronium salt was superior to other uronium salts in terms of racemization, while 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) gave the best results.
We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-pro... more We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-protection and peptide coupling.
... Louis A. Carpino and Ayman El-Faham Department of Chemistry, University of Massachusetts, Amh... more ... Louis A. Carpino and Ayman El-Faham Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01 003 Fernando Albericio Millipore Corporation, 75A Wiggins Avenue,Bedford, Massachusetts 01 730 Received September 7, 1994@ ...
Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and r... more Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and rapid continuous solution syntheses. Application to the latter methodology represents a significant improvement over the corresponding Fmoc-based method for rapid solution ...
Largely as a result of the work of Ragnarsson and associates,2 protected NJV-bis(B0C) a-amino aci... more Largely as a result of the work of Ragnarsson and associates,2 protected NJV-bis(B0C) a-amino acids, po-tentially important synthetic intermediates which incor-porate urethane protection of both available a-NH bonds, have routinely become available. It was pointed out that ...
Carbohydrates U 0500 A Facile and Eco-Friendly Method for the Synthesis of 1,2-Orthoesters of Car... more Carbohydrates U 0500 A Facile and Eco-Friendly Method for the Synthesis of 1,2-Orthoesters of Carbohydrates in Ionic Liquid.-Orthoesters such as (III) are prepared by a novel method using perbenzoylated glycopyranosyl bromide in the presence of 2,6-lutidine in ionic liquid.-(RADHAKRISHNAN*,
With the aim of the synthesis of chemically modified cyclodextrins bearing polyamine pendant grou... more With the aim of the synthesis of chemically modified cyclodextrins bearing polyamine pendant groups, potentially useful as capping agents for the preparation of nanosized metal systems or as auxiliaries for gene transfection, the reaction between the heptakis-(6-iodo)-(6-deoxy)-β-cyclodextrin and various polyamines has been explored. This synthetic approach allows obtaining materials constituted by mixtures of cyclodextrins, having different degrees of substitution, which were satisfactorily characterized by means of various complementary techniques (ESI-MS, NMR, potentiometric titration). The products obtained were successfully subjected to preliminary tests for their binding abilities towards suitable organic guests and as capping agents for the preparation of stable silver nanoparticles.
In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized... more In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, 1H NMR, 13 C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G2 for liver sarcoma, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone (3), 1,2-naphthoquinone-2-semicarbazone (4), 4-amino-1,2-naphthoquinone 2-thiosemicarbazone (7) and 4-amino-1,2-naphthoquinone-2-semicarbazone (8) are active cytotoxic agents against different cancer cell lines with IC50 values in the range of 5.73–17.67 μM. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2-naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC50 values of all these compounds.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barb... more A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of a-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit a-glucosidase activity in a reversible mixed-type manner with IC 50 between 264.07 ± 1.87 and 448.63 ± 2.46 mM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of a-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a-k, 5, and 6 showed significant to moderate anti-glycation activity (IC 50 ¼ 31.5 ± 0.81 to 554.76 ± 9.1 mM).
A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzalde... more A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine was substituted by different amines (morpholine, piperidine, or diethylamine) to afford 2,4-dichloro-6-substituted-1,3,5-triazine. The second and third chlorines were substituted by benzaldehyde derivatives in the presence of Na2CO3 as a HCl scavenger to afford the target products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or microwave irradiation to afford the di-arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in less reaction time with good yield and pu...
Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against G... more Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg 10 −teixobactin as a reference, where the nonproteinogenic residue L-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity.
The first synthesis and biological activity of a teixobactin analogue is reported. Substitution o... more The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual l-allo-enduracididine residue by the naturally occurring l-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry.
www.cheminform.wiley-vch.de Enzyme inhibiting activity X 0220 Synthetic Reactions and Structural ... more www.cheminform.wiley-vch.de Enzyme inhibiting activity X 0220 Synthetic Reactions and Structural Studies of Heterocycles Containing Nitrogen Part. 19. Synthesis of Some Pyridazinylacetic Acid Derivatives as a Novel Class of Monoamine Oxidase-A Inhibitors.-All derivatives screened for their monoamine oxidase (MAO) activity are found to be more selective to the MAO-A isoform with compound (Ia) having the highest SI value.
In the course of comparing the effectiveness of several HOAt-and HOPfp-derived coupling reagents ... more In the course of comparing the effectiveness of several HOAt-and HOPfp-derived coupling reagents by cyclization and segment condensation of model sequences, using HPLC to follow the time course and to determine the outcome in terms of oligomerization and epimerization, we found a striking improvement of the less effective HOPfp-based coupling reagent (HPyOPfp), both with regard to reaction rate and extent of epimerization, when HOAt was added.
Although Fmoc amino acid fluorides are excellent reagents for coupling of moderately hindered ami... more Although Fmoc amino acid fluorides are excellent reagents for coupling of moderately hindered amino acids (e.g., Aib-to-Aib) they are not suited for significantly more hindered systems (e.g., Aib-to-MeAib). While urethane-protected acid chlorides are inherently more reactive than the fluorides they are also ineffective for hindered systems due to competing oxazolone formation. This limitation is bypassed if urethane protection is replaced by arenesulfonyl protection and the Aib-to-MeAib and even the MeAibto-MeAib couplings are easily achieved via the appropriate acid chlorides but not the acid fluorides.
Résumé/Abstract N, N, N′, N′-Tetramethylfluoroformamidiniumhexafluoro-phosphate (TFFH) has been s... more Résumé/Abstract N, N, N′, N′-Tetramethylfluoroformamidiniumhexafluoro-phosphate (TFFH) has been shown to be an excellentpeptide-coupling reagent. It is an easily handled, crystalline compound, it has a long shelf life, and it reacts rapidly with carboxylicacids to ...
Organic Preparations and Procedures International, 2004
Ring closure reactions Ring closure reactions O 0130 A Novel and Direct Method for the Preparatio... more Ring closure reactions Ring closure reactions O 0130 A Novel and Direct Method for the Preparation of 4-Amino-1,1,3,3-tetrasubstituted Guanidines and of [1,2,4]Triazolo-Fused Heterocyclic Derivatives.-The versatility of the chloroformamidinium salts (II) for the synthesis of guanidine derivatives (III) and of [1,2,4]triazolo-fused heterocycles like (V), (VII), and (IX) is demonstrated.-(ABDUL-GHANI, M.
Recent studies described the great impact of a non-benzotriazolic family of coupling reagents bas... more Recent studies described the great impact of a non-benzotriazolic family of coupling reagents based on ethyl 2-cyano-2-(hydroxyimino)acetate, Oxyma, as a powerful coupling methodology for peptide synthesis. Here we present the synthesis and evaluation of the derived phosphonium salts O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and tetrafluoroborate (PyOxB). Both coupling reagents exhibited higher capacity to suppress racemization in various peptide models and enhanced solubility in DMF and DCM than benzotriazole-based reagents. In addition, the hexafluorophosphate analog PyOxP, combined excellent stability with outstanding efficiency in the assembly of demanding penta and decapeptides that include consecutive Aib residues. Cyclization models revealed the advantages of PyOxP, which rendered a higher percentage of cyclic material than other known potent phosphonium salts.
OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbod... more OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbodiimide (DIC) approach for the synthesis of a novel series of α-ketoamide derivatives (4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino]benzoyl amino acid ester derivatives). OxymaPure showed clear superiority to HOBt/DIC or carbodiimide alone in terms of purity and yield. The title compounds were synthesized via the ring opening of N-acylisatin. First, N-acetylisatin was reacted with 4-aminobenzoic acid under
A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for re... more A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for reactivity in solution peptide synthesis. The new triazinyloxyimino derivatives failed to activate the carboxyl group during formation of peptide bonds, but gave the corresponding N-triazinyl amino acid derivatives as a major product. The oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) uronium salt was superior to other uronium salts in terms of racemization, while 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) gave the best results.
We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-pro... more We have demonstrated that oxime-based mixed carbonates are very effective reagents for both N-protection and peptide coupling.
... Louis A. Carpino and Ayman El-Faham Department of Chemistry, University of Massachusetts, Amh... more ... Louis A. Carpino and Ayman El-Faham Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01 003 Fernando Albericio Millipore Corporation, 75A Wiggins Avenue,Bedford, Massachusetts 01 730 Received September 7, 1994@ ...
Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and r... more Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and rapid continuous solution syntheses. Application to the latter methodology represents a significant improvement over the corresponding Fmoc-based method for rapid solution ...
Largely as a result of the work of Ragnarsson and associates,2 protected NJV-bis(B0C) a-amino aci... more Largely as a result of the work of Ragnarsson and associates,2 protected NJV-bis(B0C) a-amino acids, po-tentially important synthetic intermediates which incor-porate urethane protection of both available a-NH bonds, have routinely become available. It was pointed out that ...
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