Daniela Andrei - Academia.edu (original) (raw)
Papers by Daniela Andrei
Journal of Medicinal Chemistry, 2008
A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (... more A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (NO) and which are structural analogues of the NO prodrug and anti-cancer lead compound, O 2-{2,4dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2diolate (PABA/NO), were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the anti-proliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of Sglutathionylating agents with potent anti-proliferative and S-glutathionylating activity.
The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to ... more The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'-C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard v deprotection afforded the desired analogue as 5'E isomer of the inseparable mixture of 9'RIS diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the brominationdehydrobromination strategy with pyridinium tribromide and DBU. Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp 2-Csp 3 coupling) were scarce, we were prompted to undertake model studies on Pdcatalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Zfluoroalkenes. The highest yields were obtained with PdCl 2 (dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh 3) 4. Couplings of 1,1dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product. vi
Drug development research, 2018
Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used i... more Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lyco...
Nitric Oxide, 2014
Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging f... more Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging from tumoricidal effects to treatment of heart failure. Isopropylamine-based diazeniumdiolates have been shown to produce HNO on decomposition under physiological conditions. Herein, we report the synthesis and HNO release profiles of primary alicyclic amine-based diazeniumdiolates. These compounds extend the range of known diazeniumdiolate-based HNO donors. Acetoxymethyl ester-protected diazeniumdiolates were also synthesized to improve purification and cellular uptake. The acetoxymethyl derivative of cyclopentylamine diazeniumdiolate not only showed higher cytotoxicity toward cancer cells as compared to the parent anion but was also effective in combination with tamoxifen for targeting estrogen receptor α-negative breast cancer cells.
Reactive and Functional Polymers, 2000
This paper discusses the interaction between chitosan and the polyphenols separated from spruce w... more This paper discusses the interaction between chitosan and the polyphenols separated from spruce wood bark. The chitosan and the polyphenols formed a complex and the release of the polyphenols occurred only in an alkaline medium (pH. 9) in a two-step process. Analysis of the release of the polyphenols showed that in the initial stage the diffusion occurs according to the Fick's law, while in the last stage, the process develops according to a zero-order kinetics.
The Journal of Organic Chemistry, 2006
Journal of Medicinal Chemistry, 2005
Moffatt oxidation of 2&am... more Moffatt oxidation of 2',3'-O-isopropylidene-L-adenosine and treatment of the resulting crude 5'-aldehyde with hydroxylamine followed by deprotection gave L-adenosine 5'-carboxaldehyde oximes, whose enantiomers are known to be potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. The L-adenosine and its 5'-aldehyde oxime derivatives were found to be inactive as inhibitors of AdoHcy hydrolase. Docking calculations showed that binding of L-adenosine to AdoHcy hydrolase is weaker (higher energy) and less specific (larger number of clusters) compared to D-Ado.
Bioorganic & Medicinal Chemistry, 2008
Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were pr... more Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were prepared employing cross-metathesis, Negishi couplings and Wittig reactions. Metathesis of the protected 5′-deoxy-5′-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5′-C6′ double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5′-deoxy-5′-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5′-(bromofluoromethylene)-5′deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6′-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases.
Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). ... more Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)-and HNO-generating salt of structure iPrHN-N(O)dNO-Na + (1, IPA/ NO) with BrCH 2 OAc produced a stable derivative of structure iPrHN-N(O)dNO-CH 2 OAc (2, AcOM-IPA/ NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37°C. Hydrolysis of 2 to generate HNO proceeded by at least two mechanisms. In the presence of esterase, straightforward dissociation to acetate, formaldehyde, and 1 was the dominant path. In the absence of enzyme, free 1 was not observed as an intermediate and the ratio of NO to HNO among the products approached zero. To account for this surprising result, we propose a mechanism in which base-induced removal of the N-H proton of 2 leads to acetyl group migration from oxygen to the neighboring nitrogen, followed by cleavage of the resulting rearrangement product to isopropanediazoate ion and the known HNO precursor, CH 3-C(O)-NO. The trappable yield of HNO from 2 was significantly enhanced over 1 at physiological pH, in part because the slower rate of hydrolysis for 2 generated a correspondingly lower steady-state concentration of HNO, thus, minimizing self-consumption and enhancing trapping by biological targets such as metmyoglobin and glutathione. Consistent with the chemical trapping efficiency data, micromolar concentrations of prodrug 2 displayed significantly more potent sarcomere shortening effects relative to 1 on ventricular myocytes isolated from wild-type mouse hearts, suggesting that 2 may be a promising lead compound for the development of heart failure therapies.
Reactive and Functional Polymers, 2000
This paper discusses the interaction between chitosan and the polyphenols separated from spruce w... more This paper discusses the interaction between chitosan and the polyphenols separated from spruce wood bark. The chitosan and the polyphenols formed a complex and the release of the polyphenols occurred only in an alkaline medium (pH . 9) in a two-step process. Analysis of the release of the polyphenols showed that in the initial stage the diffusion occurs according to the Fick's law, while in the last stage, the process develops according to a zero-order kinetics.
Journal of Medicinal Chemistry, 2008
A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (... more A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (NO) and which are structural analogues of the NO prodrug and anti-cancer lead compound, O 2 -{2,4dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2diolate (PABA/NO), were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the anti-proliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of Sglutathionylating agents with potent anti-proliferative and S-glutathionylating activity. sulfoxide; DEA/NO, sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; DMA/NO, sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate; PROLI/NO, disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2diolate; HBSS, Hanks's balanced salt solution; TBS-T, Tris-buffered saline-Tween 20; PBS, phosphate buffered saline; MTT, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
Journal of Medicinal Chemistry, 2008
A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (... more A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (NO) and which are structural analogues of the NO prodrug and anti-cancer lead compound, O 2-{2,4dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2diolate (PABA/NO), were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the anti-proliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of Sglutathionylating agents with potent anti-proliferative and S-glutathionylating activity.
The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to ... more The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'-C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard v deprotection afforded the desired analogue as 5'E isomer of the inseparable mixture of 9'RIS diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the brominationdehydrobromination strategy with pyridinium tribromide and DBU. Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp 2-Csp 3 coupling) were scarce, we were prompted to undertake model studies on Pdcatalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Zfluoroalkenes. The highest yields were obtained with PdCl 2 (dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh 3) 4. Couplings of 1,1dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product. vi
Drug development research, 2018
Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used i... more Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lyco...
Nitric Oxide, 2014
Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging f... more Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging from tumoricidal effects to treatment of heart failure. Isopropylamine-based diazeniumdiolates have been shown to produce HNO on decomposition under physiological conditions. Herein, we report the synthesis and HNO release profiles of primary alicyclic amine-based diazeniumdiolates. These compounds extend the range of known diazeniumdiolate-based HNO donors. Acetoxymethyl ester-protected diazeniumdiolates were also synthesized to improve purification and cellular uptake. The acetoxymethyl derivative of cyclopentylamine diazeniumdiolate not only showed higher cytotoxicity toward cancer cells as compared to the parent anion but was also effective in combination with tamoxifen for targeting estrogen receptor α-negative breast cancer cells.
Reactive and Functional Polymers, 2000
This paper discusses the interaction between chitosan and the polyphenols separated from spruce w... more This paper discusses the interaction between chitosan and the polyphenols separated from spruce wood bark. The chitosan and the polyphenols formed a complex and the release of the polyphenols occurred only in an alkaline medium (pH. 9) in a two-step process. Analysis of the release of the polyphenols showed that in the initial stage the diffusion occurs according to the Fick's law, while in the last stage, the process develops according to a zero-order kinetics.
The Journal of Organic Chemistry, 2006
Journal of Medicinal Chemistry, 2005
Moffatt oxidation of 2&am... more Moffatt oxidation of 2',3'-O-isopropylidene-L-adenosine and treatment of the resulting crude 5'-aldehyde with hydroxylamine followed by deprotection gave L-adenosine 5'-carboxaldehyde oximes, whose enantiomers are known to be potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. The L-adenosine and its 5'-aldehyde oxime derivatives were found to be inactive as inhibitors of AdoHcy hydrolase. Docking calculations showed that binding of L-adenosine to AdoHcy hydrolase is weaker (higher energy) and less specific (larger number of clusters) compared to D-Ado.
Bioorganic & Medicinal Chemistry, 2008
Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were pr... more Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were prepared employing cross-metathesis, Negishi couplings and Wittig reactions. Metathesis of the protected 5′-deoxy-5′-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5′-C6′ double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5′-deoxy-5′-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5′-(bromofluoromethylene)-5′deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6′-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases.
Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). ... more Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)-and HNO-generating salt of structure iPrHN-N(O)dNO-Na + (1, IPA/ NO) with BrCH 2 OAc produced a stable derivative of structure iPrHN-N(O)dNO-CH 2 OAc (2, AcOM-IPA/ NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37°C. Hydrolysis of 2 to generate HNO proceeded by at least two mechanisms. In the presence of esterase, straightforward dissociation to acetate, formaldehyde, and 1 was the dominant path. In the absence of enzyme, free 1 was not observed as an intermediate and the ratio of NO to HNO among the products approached zero. To account for this surprising result, we propose a mechanism in which base-induced removal of the N-H proton of 2 leads to acetyl group migration from oxygen to the neighboring nitrogen, followed by cleavage of the resulting rearrangement product to isopropanediazoate ion and the known HNO precursor, CH 3-C(O)-NO. The trappable yield of HNO from 2 was significantly enhanced over 1 at physiological pH, in part because the slower rate of hydrolysis for 2 generated a correspondingly lower steady-state concentration of HNO, thus, minimizing self-consumption and enhancing trapping by biological targets such as metmyoglobin and glutathione. Consistent with the chemical trapping efficiency data, micromolar concentrations of prodrug 2 displayed significantly more potent sarcomere shortening effects relative to 1 on ventricular myocytes isolated from wild-type mouse hearts, suggesting that 2 may be a promising lead compound for the development of heart failure therapies.
Reactive and Functional Polymers, 2000
This paper discusses the interaction between chitosan and the polyphenols separated from spruce w... more This paper discusses the interaction between chitosan and the polyphenols separated from spruce wood bark. The chitosan and the polyphenols formed a complex and the release of the polyphenols occurred only in an alkaline medium (pH . 9) in a two-step process. Analysis of the release of the polyphenols showed that in the initial stage the diffusion occurs according to the Fick's law, while in the last stage, the process develops according to a zero-order kinetics.
Journal of Medicinal Chemistry, 2008
A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (... more A number of bis(diazeniumdiolates) that we designed to release up to four moles of nitric oxide (NO) and which are structural analogues of the NO prodrug and anti-cancer lead compound, O 2 -{2,4dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2diolate (PABA/NO), were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the anti-proliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of Sglutathionylating agents with potent anti-proliferative and S-glutathionylating activity. sulfoxide; DEA/NO, sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; DMA/NO, sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate; PROLI/NO, disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2diolate; HBSS, Hanks's balanced salt solution; TBS-T, Tris-buffered saline-Tween 20; PBS, phosphate buffered saline; MTT, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide