Makhluf Haddadin - Academia.edu (original) (raw)
Papers by Makhluf Haddadin
Tetrahedron Letters, 1962
Tetrahedron letters, Jan 30, 2015
A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-... more A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential N-alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic insights, and photoluminescence properties are discussed.
ChemInform
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 2009
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 2008
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Organic letters, Jan 2, 2009
The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to prov... more The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to provide easy access to 1H-indazolones, particularly the previously unreported 2-(2-alkoxyethyl)-1H-indazol-3(2H)-ones. Mechanistic as well as optimization and reaction scope studies are reported.
Organic letters, Jan 4, 2010
A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-... more A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein iodide acts first as a nucleophile and subsequently as a leaving group.
Radiation oncology (London, England), 2007
The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ioniz... more The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ionizing radiation (IR) were determined in four colon cancer cells and in FHs74Int normal intestinal cells. Cell cycle modulation, TUNEL assay, clonogenic survival and DNA damage were examined under oxia or hypoxia. Effects on apoptotic molecules and on p-Akt and Cox-2 protein expression were investigated. The four cell lines responded differently to DCQ+IR; HT-29 cells were most resistant. Combination treatment caused significant increases in preG1 (apoptosis) in HCT-116, while G2/M arrest occurred in DLD-1. DCQ potentiated IR effects more so under hypoxia than oxia. Pre-exposure of DLD-1 to hypoxia induced 30% apoptosis, and G2/M arrest in oxia. The survival rate was 50% lower in DCQ+IR than DCQ alone and this rate further decreased under hypoxia. FHs74Int normal intestinal cells were more resistant to DCQ+IR than cancer cells.Greater ssDNA damage occurred in DLD-1 exposed to DCQ+IR under h...
International Journal of Oncology, 2004
We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotox... more We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1alpha (HIF-1alpha) expression. In this study, we evaluated the cytotoxicity, anti-angiogenic, and radiosensitization activities of the two quinoxaline 1,4-dioxides (QdNOs), BPQ and DCQ. Clonogenic survival, Matrigel, and radiosensitization assays were performed in vitro and in vivo using Lewis lung carcinoma (LLC) and EMT-6 mammary adenocarcinoma cells. Transcript and protein levels of HIF-1alpha and VEGF were determined using RT-PCR and Western blotting, respectively. DCQ showed cytotoxic effects under hypoxic conditions for both cell lines. Treatment with either drug inhibited HIF-1alpha and VEGF secretion, with DCQ being more potent than BPQ. DCQ also inhibited the formation of tube-like structures of ECV-304 endothelial cells in Matrigel by 60-80% and significantly reduced neoangiogenesis in vivo. When combined with radiation (200-1000 cGy), DCQ resulted in the death of 100% of LLC or EMT-6 cells. Using the C57BL/6 mouse model, combined treatment with DCQ and radiation delayed the growth of LLC tumors for 17 days and reduced mean tumor volume by 80% at day 20. However, BPQ combined with radiation did not induce significant tumor regression. Histological analyses revealed a significant increase in tissue necrosis in tumors treated by DCQ and radiation. These results indicate a potent anti-angiogenic and radiation modification effect of two quinoxaline dioxides. These findings should stimulate further research in other tumor models as these compounds could have potential clinical applications in cancer therapy.
Bioorganic & Medicinal Chemistry, 2014
Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response;... more Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The twostep, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H 2 O 2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC 50 values <1 lM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H 2 O 2 /HOCl/ HOBr system.
European Journal of Organic Chemistry, 2014
ABSTRACT A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxa... more ABSTRACT A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc using a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
The Journal of Organic Chemistry, 2014
Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitroben... more Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1°-aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitrobenzyl)(tritylthio)alkylamine, subsequent deprotection of the trityl moiety with TFA, and immediate treatment with aq. KOH in methanol under Davis-Beirut reaction conditions to deliver the target thiazolo-, thiazino-, or thiazepino-2H-indazole in good overall yield. Subsequent S-oxidation gives the corresponding sulfone.
Journal of Fluorescence, 2014
The absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined i... more The absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined in several solvents. The presence of electron donating or withdrawing groups on the CAC impacts spectroscopic properties. The general solvent relaxation displayed by azacyanine derivatives is in accordance with Lippert-Mataga's prediction but exception is noted in the case of protic solvent due to specific hydrogen bonding interactions. Fluorescence lifetime decay studies indicate a relaxation time in the nanosecond timescale with mono exponential decay. Donating substituents markedly increase the excited state lifetime, whereas withdrawing groups marginally decrease the excited state lifetime. Quantum chemical computations were used to explore the origins of the reactivity and spectroscopic properties of CACs; results are consistent with a model in which regioselectivity results from differences in mechanistic steps occurring after initial attack by hydroxide on the CAC.
Radiotherapy and Oncology, 2008
Background and purpose: Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxal... more Background and purpose: Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) is a radiosensitizer. Here, we investigate the mechanism of radiosensitization.
![Research paper thumbnail of ChemInform Abstract: Cyclopenta[b]pyrroles from Triazines: Synthetic and Mechanistic Studies](https://attachments.academia-assets.com/42635338/thumbnails/1.jpg)
](ChemInform, 2010
pyrroles are prepared in a two-step one-pot pyrrolidine-mediated reaction of 3,5-disubstituted 1,... more pyrroles are prepared in a two-step one-pot pyrrolidine-mediated reaction of 3,5-disubstituted 1,2,4-triazines with cyclobutanone, and the following treatment with the hydrazone or oxime (III). 3,6-Disubstituted 1,2,4-triazines undergo a 1,4-addition with cyclobutanone (II) or thiethanone (XIII) to afford the 1:1 adducts only. -(YE, L.; HADDADIN, M. J.; LODEWYK, M. W.; FERREIRA, A. J.; FETTINGER, J. C.; TANTILLO, D. J.; KURTH*, M. J.; Org. Lett. 12 (2010) 1, 164-167; Dep. Chem., Univ. Calif., Davis, CA 95616, USA; Eng.) -R. Steudel 23-156
Journal of the Chemical Society, Perkin Transactions 1, 1974
Tetrahedron Letters, 2000
A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane is de... more A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane is demonstrated by the synthesis of a variety of novel pyridino, isoquinolino, benzimidazolo, and benzthiazoloazacyanines. #
Tetrahedron Letters, 2010
The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic c... more The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic conditions, leads unexpectedly to 3,5-diaryl-(NH)-1,2,4-triazoles in moderate yields. A mechanism is proposed.
Radiation Oncology, 2009
Background: DCQ (2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide), a synthetic quinoxaline... more Background: DCQ (2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide), a synthetic quinoxaline 1,4-dioxide, enhances the cytotoxic effect of ionizing radiation (IR) in vivo and in vitro. We sought to clarify whether increased radiation-induced DNA damage, decreased rate of damage repair, and the generation of reactive oxygen species (ROS) contribute to DCQ enhancement of IR.
Tetrahedron Letters, 1962
Tetrahedron letters, Jan 30, 2015
A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-... more A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential N-alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic insights, and photoluminescence properties are discussed.
ChemInform
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 2009
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 2008
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Organic letters, Jan 2, 2009
The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to prov... more The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to provide easy access to 1H-indazolones, particularly the previously unreported 2-(2-alkoxyethyl)-1H-indazol-3(2H)-ones. Mechanistic as well as optimization and reaction scope studies are reported.
Organic letters, Jan 4, 2010
A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-... more A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein iodide acts first as a nucleophile and subsequently as a leaving group.
Radiation oncology (London, England), 2007
The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ioniz... more The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ionizing radiation (IR) were determined in four colon cancer cells and in FHs74Int normal intestinal cells. Cell cycle modulation, TUNEL assay, clonogenic survival and DNA damage were examined under oxia or hypoxia. Effects on apoptotic molecules and on p-Akt and Cox-2 protein expression were investigated. The four cell lines responded differently to DCQ+IR; HT-29 cells were most resistant. Combination treatment caused significant increases in preG1 (apoptosis) in HCT-116, while G2/M arrest occurred in DLD-1. DCQ potentiated IR effects more so under hypoxia than oxia. Pre-exposure of DLD-1 to hypoxia induced 30% apoptosis, and G2/M arrest in oxia. The survival rate was 50% lower in DCQ+IR than DCQ alone and this rate further decreased under hypoxia. FHs74Int normal intestinal cells were more resistant to DCQ+IR than cancer cells.Greater ssDNA damage occurred in DLD-1 exposed to DCQ+IR under h...
International Journal of Oncology, 2004
We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotox... more We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1alpha (HIF-1alpha) expression. In this study, we evaluated the cytotoxicity, anti-angiogenic, and radiosensitization activities of the two quinoxaline 1,4-dioxides (QdNOs), BPQ and DCQ. Clonogenic survival, Matrigel, and radiosensitization assays were performed in vitro and in vivo using Lewis lung carcinoma (LLC) and EMT-6 mammary adenocarcinoma cells. Transcript and protein levels of HIF-1alpha and VEGF were determined using RT-PCR and Western blotting, respectively. DCQ showed cytotoxic effects under hypoxic conditions for both cell lines. Treatment with either drug inhibited HIF-1alpha and VEGF secretion, with DCQ being more potent than BPQ. DCQ also inhibited the formation of tube-like structures of ECV-304 endothelial cells in Matrigel by 60-80% and significantly reduced neoangiogenesis in vivo. When combined with radiation (200-1000 cGy), DCQ resulted in the death of 100% of LLC or EMT-6 cells. Using the C57BL/6 mouse model, combined treatment with DCQ and radiation delayed the growth of LLC tumors for 17 days and reduced mean tumor volume by 80% at day 20. However, BPQ combined with radiation did not induce significant tumor regression. Histological analyses revealed a significant increase in tissue necrosis in tumors treated by DCQ and radiation. These results indicate a potent anti-angiogenic and radiation modification effect of two quinoxaline dioxides. These findings should stimulate further research in other tumor models as these compounds could have potential clinical applications in cancer therapy.
Bioorganic & Medicinal Chemistry, 2014
Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response;... more Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The twostep, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H 2 O 2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC 50 values <1 lM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H 2 O 2 /HOCl/ HOBr system.
European Journal of Organic Chemistry, 2014
ABSTRACT A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxa... more ABSTRACT A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc using a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
The Journal of Organic Chemistry, 2014
Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitroben... more Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1°-aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitrobenzyl)(tritylthio)alkylamine, subsequent deprotection of the trityl moiety with TFA, and immediate treatment with aq. KOH in methanol under Davis-Beirut reaction conditions to deliver the target thiazolo-, thiazino-, or thiazepino-2H-indazole in good overall yield. Subsequent S-oxidation gives the corresponding sulfone.
Journal of Fluorescence, 2014
The absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined i... more The absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined in several solvents. The presence of electron donating or withdrawing groups on the CAC impacts spectroscopic properties. The general solvent relaxation displayed by azacyanine derivatives is in accordance with Lippert-Mataga's prediction but exception is noted in the case of protic solvent due to specific hydrogen bonding interactions. Fluorescence lifetime decay studies indicate a relaxation time in the nanosecond timescale with mono exponential decay. Donating substituents markedly increase the excited state lifetime, whereas withdrawing groups marginally decrease the excited state lifetime. Quantum chemical computations were used to explore the origins of the reactivity and spectroscopic properties of CACs; results are consistent with a model in which regioselectivity results from differences in mechanistic steps occurring after initial attack by hydroxide on the CAC.
Radiotherapy and Oncology, 2008
Background and purpose: Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxal... more Background and purpose: Previously, we have reported that 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) is a radiosensitizer. Here, we investigate the mechanism of radiosensitization.
ChemInform, 2010
pyrroles are prepared in a two-step one-pot pyrrolidine-mediated reaction of 3,5-disubstituted 1,... more pyrroles are prepared in a two-step one-pot pyrrolidine-mediated reaction of 3,5-disubstituted 1,2,4-triazines with cyclobutanone, and the following treatment with the hydrazone or oxime (III). 3,6-Disubstituted 1,2,4-triazines undergo a 1,4-addition with cyclobutanone (II) or thiethanone (XIII) to afford the 1:1 adducts only. -(YE, L.; HADDADIN, M. J.; LODEWYK, M. W.; FERREIRA, A. J.; FETTINGER, J. C.; TANTILLO, D. J.; KURTH*, M. J.; Org. Lett. 12 (2010) 1, 164-167; Dep. Chem., Univ. Calif., Davis, CA 95616, USA; Eng.) -R. Steudel 23-156
Journal of the Chemical Society, Perkin Transactions 1, 1974
Tetrahedron Letters, 2000
A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane is de... more A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane is demonstrated by the synthesis of a variety of novel pyridino, isoquinolino, benzimidazolo, and benzthiazoloazacyanines. #
Tetrahedron Letters, 2010
The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic c... more The reaction of 3,6-diaryl-1,2,4,5-tetrazines and 2-aryl substituted acetonitriles, under basic conditions, leads unexpectedly to 3,5-diaryl-(NH)-1,2,4-triazoles in moderate yields. A mechanism is proposed.
Radiation Oncology, 2009
Background: DCQ (2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide), a synthetic quinoxaline... more Background: DCQ (2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide), a synthetic quinoxaline 1,4-dioxide, enhances the cytotoxic effect of ionizing radiation (IR) in vivo and in vitro. We sought to clarify whether increased radiation-induced DNA damage, decreased rate of damage repair, and the generation of reactive oxygen species (ROS) contribute to DCQ enhancement of IR.