Angelos Dovletoglou | University of North Carolina at Chapel Hill (original) (raw)

Papers by Angelos Dovletoglou

Research paper thumbnail of Novel cis-directed, four-electron dioxo oxidant

Journal of the American Chemical Society, 1990

Research paper thumbnail of Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic targets

Journal of Controlled Release, 2015

Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in... more Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is currently in Phase 1 clinical trials in relapsed refractory acute leukemia patients and is administered as a continuous IV infusion (CIV). The studies herein investigated alternatives to CIV administration of pinometostat to improve patient convenience. Various sustained release technologies were considered, and based on the required dose size as well as practical considerations, subcutaneous (SC) bolus administration of a solution formulation was selected for further evaluation in preclinical studies. SC administration offered improved exposure and complete bioavailability of pinometostat relative to CIV and oral administration. These findings warranted further evaluation in rat xenograft models of MLL-r leukemia. SC dosing in xenograft models demonstrated inhibition of MLL-r tumor growth and inhibition of pharmacodynamic markers of DOT1L activity. However, a dosing frequency of thrice daily (t.i.d) was required in these studies to elicit optimal inhibition of DOT1L target genes and tumor growth inhibition. Development of an extended release formulation may prove useful in the further optimization of the SC delivery of pinometostat, moving towards a more convenient dosing paradigm for patients.

Research paper thumbnail of Transition Metal-Mediated Separation of Isomeric Pneumocandins by Capillary Electrochromatography

Journal of High Resolution Chromatography, 1999

Research paper thumbnail of Development of Practical HPLC Methods for Analysis and Quality Assessment of the Novel Carbonic Anhydrase Inhibitor MK-0507 and the Acetamidosulfonamide Intermediate

Journal of Liquid Chromatography, 1995

MK-0507 (Dorzolamide HCl, (4S,6S)-4-Ethylamino-5,6-dihydro-6-methyl-4H-thieno-[2,3-b] thiopyran-2... more MK-0507 (Dorzolamide HCl, (4S,6S)-4-Ethylamino-5,6-dihydro-6-methyl-4H-thieno-[2,3-b] thiopyran-2-sulfonamide 7,7-dioxide hydrochloride) is the first topically active, water-soluble, carbonic anhydrase inhibitor to be developed for the treatment of glaucoma and ocular hypertension. Dorzolamide HCl is an effective and well tolerated agent as monotherapy for patients who cannot tolerate ophthalmic beta-blockers, and for those who need add-on therapy to beta-blockers. The steps taken in the development and validation of a fast and rugged reverse-phase HPLC method for the analysis and quality assessment of MK-0507 drug substance and acetamidosulfonamide intermediate are described. Four columns were used during the development: Du Pont Zorbax C-18, Rainin Microsorb C-8, Perkin Elmer CR-C8 and YMC4. The last two columns showed excellent resolution, peak shape, and precision. The selected HPLC method for acetamidosulfonamide, using the Perkin Elmer CR-C8 column, was validated with respect to linearity, limit of detection (LOD) and limit of quantitation (LOQ). The selected HPLC method for the MK-0507 drug substance using the Perkin Elmer CR-C8 column was validated with respect to linearity, LOD, LOQ, precision on an injection-to-injection basis, and on a day-to-day basis, selectivity and accuracy.The method is rugged with respect to solution stability, variations in buffer concentration, flow rate, column-to-column variability and column temperature. The relative response factor for the cis-isomer of MK-0507 and the desethyl impurity were also determined in order to quantitatively measure the levels of these impurities in MK-0507. There are three possible stereoisomers of MK-0507 (4S,6S): the enantiomer 4R,6R and the cis-diastereoisomers 4S,6R and 4R,6S. The chiral HPLC method separates the two trans-diastereoisomers, and the two cis-diastereo-isomers; however, in the same chiral method the 4R,6R and 4R,6S stereoisomers coelute.

Research paper thumbnail of Novel cis-directed, four-electron dioxo oxidant

Journal of the American Chemical Society, 1990

Research paper thumbnail of Mechanism of cis-directed four-electron oxidation by a trans-dioxo complex of ruthenium(VI)

Journal of the American Chemical Society, 1994

Mechanism of cis-Directed Four-Electron Oxidation by a ... Contribution from the Department of Ch... more Mechanism of cis-Directed Four-Electron Oxidation by a ... Contribution from the Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290 Received July 23, 1992. Revised Manuscript Received May 17, 1993'

Research paper thumbnail of Evaluating HPLC Assay Robustness with Experimental Design

Journal of Liquid Chromatography & Related Technologies, 2003

... Section 9; 4. Nsengiyumva, C., DeBeer, JO, Van de Wauw, W. and Parmentier, AJ 1997. Chromatog... more ... Section 9; 4. Nsengiyumva, C., DeBeer, JO, Van de Wauw, W. and Parmentier, AJ 1997. Chromatographia, 44: 634–644. [CrossRef], [Web of Science ®]; 5. Osborne, LM and Miyakawa, TW 1997. J. Liq. Chromatogr. Relat. Technol., 20: 501–509. [Taylor & Francis Online], [Web of ...

Research paper thumbnail of Modeling the Selection of Fractions During Preparative HPLC of a Semisynthetic Pneumocandin

Journal of Liquid Chromatography & Related Technologies, 2001

ABSTRACT

Research paper thumbnail of Coordination and Redox Chemistry of Substituted-Polypyridyl Complexes of Ruthenium

Inorganic Chemistry, 1996

The complexes [Ru(tpy)(acac)(Cl)], [Ru(tpy)(acac)(H(2)O)](PF(6)) (tpy = 2,2&a... more The complexes [Ru(tpy)(acac)(Cl)], [Ru(tpy)(acac)(H(2)O)](PF(6)) (tpy = 2,2',2"-terpyridine, acacH = 2,4 pentanedione) [Ru(tpy)(C(2)O(4))(H(2)O)] (C(2)O(4)(2)(-) = oxalato dianion), [Ru(tpy)(dppene)(Cl)](PF(6)) (dppene = cis-1,2-bis(diphenylphosphino)ethylene), [Ru(tpy)(dppene)(H(2)O)](PF(6))(2), [Ru(tpy)(C(2)O(4))(py)], [Ru(tpy)(acac)(py)](ClO(4)), [Ru(tpy)(acac)(NO(2))], [Ru(tpy)(acac)(NO)](PF(6))(2), and [Ru(tpy)(PSCS)Cl] (PSCS = 1-pyrrolidinedithiocarbamate anion) have been prepared and characterized by cyclic voltammetry and UV-visible and FTIR spectroscopy. [Ru(tpy)(acac)(NO(2))](+) is stable with respect to oxidation of coordinated NO(2)(-) on the cyclic voltammetric time scale. The nitrosyl [Ru(tpy)(acac)(NO)](2+) falls on an earlier correlation between nu(NO) (1914 cm(-)(1) in KBr) and E(1/2) for the first nitrosyl-based reduction 0.02 V vs SSCE. Oxalate ligand is lost from [Ru(II)(tpy)(C(2)O(4))(H(2)O)] to give [Ru(tpy)(H(2)O)(3)](2+). The Ru(III/II) and Ru(IV/III) couples of the aqua complexes are pH dependent. At pH 7.0, E(1/2) values are 0.43 V vs NHE for [Ru(III)(tpy)(acac)(OH)](+)/[Ru(II)(tpy)(acac)(H(2)O)](+), 0.80 V for [Ru(IV)(tpy)(acac)(O)](+)/[Ru(III)(tpy)(acac)(OH)](+), 0.16 V for [Ru(III)(tpy)(C(2)O(4))(OH)]/[Ru(II)(tpy)(C(2)O(4))(H(2)O)], and 0.45 V for [Ru(IV)(tpy)(C(2)O(4))(O)]/[Ru(III)(tpy)(C(2)O(4))(OH)]. Plots of E(1/2) vs pH define regions of stability for the various oxidation states and the pK(a) values of aqua and hydroxo forms. These measurements reveal that C(2)O(4)(2)(-) and acac(-) are electron donating to Ru(III) relative to bpy. Comparisons with redox potentials for 21 related polypyridyl couples reveal the influence of ligand changes on the potentials of the Ru(IV/III) and Ru(III/II) couples and the difference between them, DeltaE(1/2). The majority of the effect appears in the Ru(III/II) couple. ()A linear correlation exists between DeltaE(1/2) and the sum of a set of ligand parameters defined by Lever et al., SigmaE(i)(L(i)), for the series of complexes, but there is a dramatic change in slope at DeltaE(1/2) approximately -0.11 V and SigmaE(i)(L(i)) = 1.06 V. Extrapolation of the plot of DeltaE(1/2) vs SigmaE(i)(L(i)) suggests that there may be ligand environments in which Ru(III) is unstable with respect to disproportionation into Ru(IV) and Ru(II). This would make the two-electron Ru(IV)O/Ru(II)OH(2) couple more strongly oxidizing than the one-electron Ru(IV)O/Ru(III)OH couple.

Research paper thumbnail of Preparation of phosphoraniminato complexes containing polypyridyl ligands. Nitrogen atom transfer from dichloronitrido(terpyridine)osmium(1+)

Inorganic Chemistry, 1991

... 3 A parallel, nitrogen atom transfer chemistry has been established for complexes of Fe(V),4 ... more ... 3 A parallel, nitrogen atom transfer chemistry has been established for complexes of Fe(V),4 Mo(VI),' and OS(VI).~ We recently ... of Chemistry Mohammed Bakir The University of North Carolina Peter S. White Chapel Hill, North Carolina 27599-3290 Angelos Dovletoglou Thomas ...

Research paper thumbnail of Redox and spectral properties of the four-electron oxidant trans-aquadioxo(terpyridine)ruthenium(2+) diperchlorate

Inorganic Chemistry, 1992

Contribution from the Department of Chemistry, The University of North Carolina, Chapel Hill, Nor... more Contribution from the Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599-3290 ... Redox and Spectral Properties of the Four-Electron Oxidant ... (tpy)(0)(Hz0)z]z+/[Ru11'(tpy)(HzO)3]3+, and [Ru11'(tpy)(H20)3]3+/[R~*1(tpy)(HZ0)3]2+ ...

Research paper thumbnail of Practical aspects of fast HPLC separations for pharmaceutical process development using monolithic columns

Analytica Chimica Acta, 2004

A large number of samples can be generated during pharmaceutical process development. Fast separa... more A large number of samples can be generated during pharmaceutical process development. Fast separation for these samples is usually challenging due to the complexity of sample matrix, which requires high efficiency as well as high speed. Monolithic columns (E. Merck, Germany) were investigated as a possible tool for reducing separation time in reversed-phase HPLC without significantly sacrificing efficiency or resolution. Both van Deemter plots and separations of alkyl benzenes and in-process samples showed that monolithic columns were suitable for fast separations without significantly compromising resolution. Practical parameters including the pressure drop, retention factor, selectivity, and tailing factor of monolithic columns (Chromolith type) were compared to those of conventional YMC 150 mm × 4.6 mm (3-m particles) and 250 mm × 4.6 mm (5-m particles) packed columns. The batch-to-batch reproducibility of the 100 mm × 4.6 mm Chromolith columns from five randomly ordered batches was also compared to the 250 mm × 4.6 mm YMC particle-packed columns. Fast and efficient separations of complicated process samples including crude drug substances, reaction mixtures, and crystallized mother liquors were demonstrated for both monolithic columns and conventional packed columns. The analysis times were decreased by three to seven times on the coupled monolithic columns, while maintaining the comparable resolution to typical 5-m particle-packed 250 mm × 4.6 mm columns.

Research paper thumbnail of Novel cis-directed, four-electron dioxo oxidant

Journal of the American Chemical Society, 1990

Research paper thumbnail of Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic targets

Journal of Controlled Release, 2015

Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in... more Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is currently in Phase 1 clinical trials in relapsed refractory acute leukemia patients and is administered as a continuous IV infusion (CIV). The studies herein investigated alternatives to CIV administration of pinometostat to improve patient convenience. Various sustained release technologies were considered, and based on the required dose size as well as practical considerations, subcutaneous (SC) bolus administration of a solution formulation was selected for further evaluation in preclinical studies. SC administration offered improved exposure and complete bioavailability of pinometostat relative to CIV and oral administration. These findings warranted further evaluation in rat xenograft models of MLL-r leukemia. SC dosing in xenograft models demonstrated inhibition of MLL-r tumor growth and inhibition of pharmacodynamic markers of DOT1L activity. However, a dosing frequency of thrice daily (t.i.d) was required in these studies to elicit optimal inhibition of DOT1L target genes and tumor growth inhibition. Development of an extended release formulation may prove useful in the further optimization of the SC delivery of pinometostat, moving towards a more convenient dosing paradigm for patients.

Research paper thumbnail of Transition Metal-Mediated Separation of Isomeric Pneumocandins by Capillary Electrochromatography

Journal of High Resolution Chromatography, 1999

Research paper thumbnail of Development of Practical HPLC Methods for Analysis and Quality Assessment of the Novel Carbonic Anhydrase Inhibitor MK-0507 and the Acetamidosulfonamide Intermediate

Journal of Liquid Chromatography, 1995

MK-0507 (Dorzolamide HCl, (4S,6S)-4-Ethylamino-5,6-dihydro-6-methyl-4H-thieno-[2,3-b] thiopyran-2... more MK-0507 (Dorzolamide HCl, (4S,6S)-4-Ethylamino-5,6-dihydro-6-methyl-4H-thieno-[2,3-b] thiopyran-2-sulfonamide 7,7-dioxide hydrochloride) is the first topically active, water-soluble, carbonic anhydrase inhibitor to be developed for the treatment of glaucoma and ocular hypertension. Dorzolamide HCl is an effective and well tolerated agent as monotherapy for patients who cannot tolerate ophthalmic beta-blockers, and for those who need add-on therapy to beta-blockers. The steps taken in the development and validation of a fast and rugged reverse-phase HPLC method for the analysis and quality assessment of MK-0507 drug substance and acetamidosulfonamide intermediate are described. Four columns were used during the development: Du Pont Zorbax C-18, Rainin Microsorb C-8, Perkin Elmer CR-C8 and YMC4. The last two columns showed excellent resolution, peak shape, and precision. The selected HPLC method for acetamidosulfonamide, using the Perkin Elmer CR-C8 column, was validated with respect to linearity, limit of detection (LOD) and limit of quantitation (LOQ). The selected HPLC method for the MK-0507 drug substance using the Perkin Elmer CR-C8 column was validated with respect to linearity, LOD, LOQ, precision on an injection-to-injection basis, and on a day-to-day basis, selectivity and accuracy.The method is rugged with respect to solution stability, variations in buffer concentration, flow rate, column-to-column variability and column temperature. The relative response factor for the cis-isomer of MK-0507 and the desethyl impurity were also determined in order to quantitatively measure the levels of these impurities in MK-0507. There are three possible stereoisomers of MK-0507 (4S,6S): the enantiomer 4R,6R and the cis-diastereoisomers 4S,6R and 4R,6S. The chiral HPLC method separates the two trans-diastereoisomers, and the two cis-diastereo-isomers; however, in the same chiral method the 4R,6R and 4R,6S stereoisomers coelute.

Research paper thumbnail of Novel cis-directed, four-electron dioxo oxidant

Journal of the American Chemical Society, 1990

Research paper thumbnail of Mechanism of cis-directed four-electron oxidation by a trans-dioxo complex of ruthenium(VI)

Journal of the American Chemical Society, 1994

Mechanism of cis-Directed Four-Electron Oxidation by a ... Contribution from the Department of Ch... more Mechanism of cis-Directed Four-Electron Oxidation by a ... Contribution from the Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290 Received July 23, 1992. Revised Manuscript Received May 17, 1993'

Research paper thumbnail of Evaluating HPLC Assay Robustness with Experimental Design

Journal of Liquid Chromatography & Related Technologies, 2003

... Section 9; 4. Nsengiyumva, C., DeBeer, JO, Van de Wauw, W. and Parmentier, AJ 1997. Chromatog... more ... Section 9; 4. Nsengiyumva, C., DeBeer, JO, Van de Wauw, W. and Parmentier, AJ 1997. Chromatographia, 44: 634–644. [CrossRef], [Web of Science ®]; 5. Osborne, LM and Miyakawa, TW 1997. J. Liq. Chromatogr. Relat. Technol., 20: 501–509. [Taylor & Francis Online], [Web of ...

Research paper thumbnail of Modeling the Selection of Fractions During Preparative HPLC of a Semisynthetic Pneumocandin

Journal of Liquid Chromatography & Related Technologies, 2001

ABSTRACT

Research paper thumbnail of Coordination and Redox Chemistry of Substituted-Polypyridyl Complexes of Ruthenium

Inorganic Chemistry, 1996

The complexes [Ru(tpy)(acac)(Cl)], [Ru(tpy)(acac)(H(2)O)](PF(6)) (tpy = 2,2&a... more The complexes [Ru(tpy)(acac)(Cl)], [Ru(tpy)(acac)(H(2)O)](PF(6)) (tpy = 2,2',2"-terpyridine, acacH = 2,4 pentanedione) [Ru(tpy)(C(2)O(4))(H(2)O)] (C(2)O(4)(2)(-) = oxalato dianion), [Ru(tpy)(dppene)(Cl)](PF(6)) (dppene = cis-1,2-bis(diphenylphosphino)ethylene), [Ru(tpy)(dppene)(H(2)O)](PF(6))(2), [Ru(tpy)(C(2)O(4))(py)], [Ru(tpy)(acac)(py)](ClO(4)), [Ru(tpy)(acac)(NO(2))], [Ru(tpy)(acac)(NO)](PF(6))(2), and [Ru(tpy)(PSCS)Cl] (PSCS = 1-pyrrolidinedithiocarbamate anion) have been prepared and characterized by cyclic voltammetry and UV-visible and FTIR spectroscopy. [Ru(tpy)(acac)(NO(2))](+) is stable with respect to oxidation of coordinated NO(2)(-) on the cyclic voltammetric time scale. The nitrosyl [Ru(tpy)(acac)(NO)](2+) falls on an earlier correlation between nu(NO) (1914 cm(-)(1) in KBr) and E(1/2) for the first nitrosyl-based reduction 0.02 V vs SSCE. Oxalate ligand is lost from [Ru(II)(tpy)(C(2)O(4))(H(2)O)] to give [Ru(tpy)(H(2)O)(3)](2+). The Ru(III/II) and Ru(IV/III) couples of the aqua complexes are pH dependent. At pH 7.0, E(1/2) values are 0.43 V vs NHE for [Ru(III)(tpy)(acac)(OH)](+)/[Ru(II)(tpy)(acac)(H(2)O)](+), 0.80 V for [Ru(IV)(tpy)(acac)(O)](+)/[Ru(III)(tpy)(acac)(OH)](+), 0.16 V for [Ru(III)(tpy)(C(2)O(4))(OH)]/[Ru(II)(tpy)(C(2)O(4))(H(2)O)], and 0.45 V for [Ru(IV)(tpy)(C(2)O(4))(O)]/[Ru(III)(tpy)(C(2)O(4))(OH)]. Plots of E(1/2) vs pH define regions of stability for the various oxidation states and the pK(a) values of aqua and hydroxo forms. These measurements reveal that C(2)O(4)(2)(-) and acac(-) are electron donating to Ru(III) relative to bpy. Comparisons with redox potentials for 21 related polypyridyl couples reveal the influence of ligand changes on the potentials of the Ru(IV/III) and Ru(III/II) couples and the difference between them, DeltaE(1/2). The majority of the effect appears in the Ru(III/II) couple. ()A linear correlation exists between DeltaE(1/2) and the sum of a set of ligand parameters defined by Lever et al., SigmaE(i)(L(i)), for the series of complexes, but there is a dramatic change in slope at DeltaE(1/2) approximately -0.11 V and SigmaE(i)(L(i)) = 1.06 V. Extrapolation of the plot of DeltaE(1/2) vs SigmaE(i)(L(i)) suggests that there may be ligand environments in which Ru(III) is unstable with respect to disproportionation into Ru(IV) and Ru(II). This would make the two-electron Ru(IV)O/Ru(II)OH(2) couple more strongly oxidizing than the one-electron Ru(IV)O/Ru(III)OH couple.

Research paper thumbnail of Preparation of phosphoraniminato complexes containing polypyridyl ligands. Nitrogen atom transfer from dichloronitrido(terpyridine)osmium(1+)

Inorganic Chemistry, 1991

... 3 A parallel, nitrogen atom transfer chemistry has been established for complexes of Fe(V),4 ... more ... 3 A parallel, nitrogen atom transfer chemistry has been established for complexes of Fe(V),4 Mo(VI),' and OS(VI).~ We recently ... of Chemistry Mohammed Bakir The University of North Carolina Peter S. White Chapel Hill, North Carolina 27599-3290 Angelos Dovletoglou Thomas ...

Research paper thumbnail of Redox and spectral properties of the four-electron oxidant trans-aquadioxo(terpyridine)ruthenium(2+) diperchlorate

Inorganic Chemistry, 1992

Contribution from the Department of Chemistry, The University of North Carolina, Chapel Hill, Nor... more Contribution from the Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599-3290 ... Redox and Spectral Properties of the Four-Electron Oxidant ... (tpy)(0)(Hz0)z]z+/[Ru11'(tpy)(HzO)3]3+, and [Ru11'(tpy)(H20)3]3+/[R~*1(tpy)(HZ0)3]2+ ...

Research paper thumbnail of Practical aspects of fast HPLC separations for pharmaceutical process development using monolithic columns

Analytica Chimica Acta, 2004

A large number of samples can be generated during pharmaceutical process development. Fast separa... more A large number of samples can be generated during pharmaceutical process development. Fast separation for these samples is usually challenging due to the complexity of sample matrix, which requires high efficiency as well as high speed. Monolithic columns (E. Merck, Germany) were investigated as a possible tool for reducing separation time in reversed-phase HPLC without significantly sacrificing efficiency or resolution. Both van Deemter plots and separations of alkyl benzenes and in-process samples showed that monolithic columns were suitable for fast separations without significantly compromising resolution. Practical parameters including the pressure drop, retention factor, selectivity, and tailing factor of monolithic columns (Chromolith type) were compared to those of conventional YMC 150 mm × 4.6 mm (3-m particles) and 250 mm × 4.6 mm (5-m particles) packed columns. The batch-to-batch reproducibility of the 100 mm × 4.6 mm Chromolith columns from five randomly ordered batches was also compared to the 250 mm × 4.6 mm YMC particle-packed columns. Fast and efficient separations of complicated process samples including crude drug substances, reaction mixtures, and crystallized mother liquors were demonstrated for both monolithic columns and conventional packed columns. The analysis times were decreased by three to seven times on the coupled monolithic columns, while maintaining the comparable resolution to typical 5-m particle-packed 250 mm × 4.6 mm columns.