TPS7077 Background: Patients with relapsed and/or refractory (r/r) myelodysplastic syndrome (MDS)... more TPS7077 Background: Patients with relapsed and/or refractory (r/r) myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) who are not candidates for stem-cell transplantation have dismal outcomes. Novel therapies are needed. The nucleoside analogue NTX-301 (5-aza-4’-thio-2’-deoxycytidine or Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in re-activation of tumor suppressor genes. Preclinical data suggest a correlation between NTX-301 activity in leukemia xenograft models and decreased levels of DNMT1. NTX-301 offers an improvement over traditional DNA methyltransferase inhibitors (azacitidine, decitabine) by vi...
Chiral hydrazones 1 reacted with aryl-or alkyl-lithiums at −78°C in a short reaction time, within... more Chiral hydrazones 1 reacted with aryl-or alkyl-lithiums at −78°C in a short reaction time, within 10 min, to afford arylated or alkylated chiral hydrazines 3 with extremely high diastereoselectivity (up to >99% de) and high chemical yields. The hydrazines are readily converted to chiral amino alcohols 4. Chirality 12:404-407, 2000.
Introduction: While intensive induction chemotherapy has been standard-or-care for patients with ... more Introduction: While intensive induction chemotherapy has been standard-or-care for patients with acute myeloid leukemia (AML), intensive regimens have often been limited in elderly patients with comorbidities. As an alternative option, less intensive hypomethylating agents (HMAs), decitabine (DAC) and azacitidine (AZA), are currently being used in these unfit patients. However, their low response rates and adverse events when administered alone suggest a need to develop novel HMAs that elicit enhanced efficacy and reduced mortality. A recent study demonstrated pharmacological improvements of a novel 4′-thio-modified analog, 5-aza-4′-thio-2′-deoxycytidine (hereafter NTX-301), including enhanced chemical stability and incorporation into DNA and improved preclinical efficacy (Thottassery, 2014). However, the mechanism of action (MoA) of NTX-301 has not yet been understood. Herein, we aim to thoroughly investigate the preclinical efficacy and MoAs of NTX-301 in AML through comparative a...
An efficient procedure for the preparation of Z-enamides has been developed, involving the reacti... more An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible σ-alkylamidopalladium intermediates, leading to Zand E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The-hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Zand E-enamides was observed to be largely dependent on the substrates' substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801.
Diastereo-and enantioselective pinacol coupling reactions of chiral α-ketoamides mediated by sama... more Diastereo-and enantioselective pinacol coupling reactions of chiral α-ketoamides mediated by samarium diiodide afforded extremely high diastereoselectivities. Enantiopure (
Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed t... more Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed three-component reaction with 1-alkynes and amines to produce the corresponding phosphoryl amidines in high yields. A range of fruitful applicability of the produced amidines was also demonstrated such as an alkoxide exchange and asymmetric R-alkylation of optically active BINOL-derived amidines.
Amino acids U 0400 Efficient Enantioselective Synthesis of α-Hydroxy-β-amino Acids Using the Clai... more Amino acids U 0400 Efficient Enantioselective Synthesis of α-Hydroxy-β-amino Acids Using the Claisen and Curtius Rearrangements.-Precursors of type (III) and (VII) are prepared via Claisen rearrangement of chiral allylic ester substrates. They are treated according to conditions A)-C) including Curtius rearrangement, followed by transformation into the Cbz-protected target compounds [cf. (V)]. The latter are of interest as synthons of pharmaceuticals.-(
ABSTRACT This article summarizes the results of our recent studies on development of new reaction... more ABSTRACT This article summarizes the results of our recent studies on development of new reactions with samarium diiodide utilizing its characteristic reactivities. The reactions dealt in this article include novel carbon-carbon bond forming reactions of both intramolecular and intermolecular types, and functional group transformations. Also, some examples of asymmetric synthesis by intermolecular pinacol coupling reactions and hydrodimerization of alpha,beta-unsaturated carbonyl compounds are presented here. 1 Introduction 2 Reactions Involving Intermolecular C-C Bond Formation 2.1 Coupling Reaction of Isothiocyanates or Isocyanates with SmI2 2.2 A Facile Synthesis of 4-Hydroxy-(E)-alkenoic Esters 2.3 Highly Diastereoselective Intermolecular Pinacol Coupling Reactions 2.4 Asymmetric Hydrodimerizations of alpha,beta-Unsaturated Carbonyl Compounds 2.5 A Novel C-C Bond Formation Process Mediated by SmI2: Effective Approach to Baylis-Hillman Adducts 3 Reactions Involving Intramolecular C-C Bond Formation 3.1 Reductive Intramolecular Cyclization of alpha-Bromo Silyl Ethers 3.2 Intramolecular Reductive Cyclization of beta-Ketoisothio-cyanates Promoted by Samarium Diiodide 4 Reactions Proceeding without the Formation of a C-C Bond 4.1 Novel Reduction of Isothiocyanates to Thioformamides with SmI2 4.2 A Convenient Coupling of Isocyanates with Tertiary Alcohols with a Catalytic Amount of SmI2 4.3 Efficient Synthesis of Iodohydrins by Selective Cleavage of Epoxides with Samarium Iodide Complex 4.4 Highly Regioselective Cleavages and Iodinations of Cyclic Ethers with SmI2 4.5 Facile Synthesis of Enol Ethers by Cleavage of alpha-Bromoacetals and alpha-Bromoketals Mediated by SmI2 5 Conclusion.
TPS7077 Background: Patients with relapsed and/or refractory (r/r) myelodysplastic syndrome (MDS)... more TPS7077 Background: Patients with relapsed and/or refractory (r/r) myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) who are not candidates for stem-cell transplantation have dismal outcomes. Novel therapies are needed. The nucleoside analogue NTX-301 (5-aza-4’-thio-2’-deoxycytidine or Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in re-activation of tumor suppressor genes. Preclinical data suggest a correlation between NTX-301 activity in leukemia xenograft models and decreased levels of DNMT1. NTX-301 offers an improvement over traditional DNA methyltransferase inhibitors (azacitidine, decitabine) by vi...
Chiral hydrazones 1 reacted with aryl-or alkyl-lithiums at −78°C in a short reaction time, within... more Chiral hydrazones 1 reacted with aryl-or alkyl-lithiums at −78°C in a short reaction time, within 10 min, to afford arylated or alkylated chiral hydrazines 3 with extremely high diastereoselectivity (up to >99% de) and high chemical yields. The hydrazines are readily converted to chiral amino alcohols 4. Chirality 12:404-407, 2000.
Introduction: While intensive induction chemotherapy has been standard-or-care for patients with ... more Introduction: While intensive induction chemotherapy has been standard-or-care for patients with acute myeloid leukemia (AML), intensive regimens have often been limited in elderly patients with comorbidities. As an alternative option, less intensive hypomethylating agents (HMAs), decitabine (DAC) and azacitidine (AZA), are currently being used in these unfit patients. However, their low response rates and adverse events when administered alone suggest a need to develop novel HMAs that elicit enhanced efficacy and reduced mortality. A recent study demonstrated pharmacological improvements of a novel 4′-thio-modified analog, 5-aza-4′-thio-2′-deoxycytidine (hereafter NTX-301), including enhanced chemical stability and incorporation into DNA and improved preclinical efficacy (Thottassery, 2014). However, the mechanism of action (MoA) of NTX-301 has not yet been understood. Herein, we aim to thoroughly investigate the preclinical efficacy and MoAs of NTX-301 in AML through comparative a...
An efficient procedure for the preparation of Z-enamides has been developed, involving the reacti... more An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible σ-alkylamidopalladium intermediates, leading to Zand E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The-hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Zand E-enamides was observed to be largely dependent on the substrates' substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801.
Diastereo-and enantioselective pinacol coupling reactions of chiral α-ketoamides mediated by sama... more Diastereo-and enantioselective pinacol coupling reactions of chiral α-ketoamides mediated by samarium diiodide afforded extremely high diastereoselectivities. Enantiopure (
Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed t... more Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed three-component reaction with 1-alkynes and amines to produce the corresponding phosphoryl amidines in high yields. A range of fruitful applicability of the produced amidines was also demonstrated such as an alkoxide exchange and asymmetric R-alkylation of optically active BINOL-derived amidines.
Amino acids U 0400 Efficient Enantioselective Synthesis of α-Hydroxy-β-amino Acids Using the Clai... more Amino acids U 0400 Efficient Enantioselective Synthesis of α-Hydroxy-β-amino Acids Using the Claisen and Curtius Rearrangements.-Precursors of type (III) and (VII) are prepared via Claisen rearrangement of chiral allylic ester substrates. They are treated according to conditions A)-C) including Curtius rearrangement, followed by transformation into the Cbz-protected target compounds [cf. (V)]. The latter are of interest as synthons of pharmaceuticals.-(
ABSTRACT This article summarizes the results of our recent studies on development of new reaction... more ABSTRACT This article summarizes the results of our recent studies on development of new reactions with samarium diiodide utilizing its characteristic reactivities. The reactions dealt in this article include novel carbon-carbon bond forming reactions of both intramolecular and intermolecular types, and functional group transformations. Also, some examples of asymmetric synthesis by intermolecular pinacol coupling reactions and hydrodimerization of alpha,beta-unsaturated carbonyl compounds are presented here. 1 Introduction 2 Reactions Involving Intermolecular C-C Bond Formation 2.1 Coupling Reaction of Isothiocyanates or Isocyanates with SmI2 2.2 A Facile Synthesis of 4-Hydroxy-(E)-alkenoic Esters 2.3 Highly Diastereoselective Intermolecular Pinacol Coupling Reactions 2.4 Asymmetric Hydrodimerizations of alpha,beta-Unsaturated Carbonyl Compounds 2.5 A Novel C-C Bond Formation Process Mediated by SmI2: Effective Approach to Baylis-Hillman Adducts 3 Reactions Involving Intramolecular C-C Bond Formation 3.1 Reductive Intramolecular Cyclization of alpha-Bromo Silyl Ethers 3.2 Intramolecular Reductive Cyclization of beta-Ketoisothio-cyanates Promoted by Samarium Diiodide 4 Reactions Proceeding without the Formation of a C-C Bond 4.1 Novel Reduction of Isothiocyanates to Thioformamides with SmI2 4.2 A Convenient Coupling of Isocyanates with Tertiary Alcohols with a Catalytic Amount of SmI2 4.3 Efficient Synthesis of Iodohydrins by Selective Cleavage of Epoxides with Samarium Iodide Complex 4.4 Highly Regioselective Cleavages and Iodinations of Cyclic Ethers with SmI2 4.5 Facile Synthesis of Enol Ethers by Cleavage of alpha-Bromoacetals and alpha-Bromoketals Mediated by SmI2 5 Conclusion.
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Papers by Doo Young Jung