Enantioselective Synthesis of Chiral α‐Alkylthiomalonates via a Phase‐Transfer‐Catalyzed α‐Sulfenylation of α‐Alkylmalonates

So Hyun Jung, Byungsoo Kim, Cheonhyoung Park, Jeongseok Kim, Min Woo Ha, Suckchang Hong, and Hyeung-geun Park*

Research Institute of Pharmaceutical Sciences and College of Pharmacy Seoul National University, Seoul, Korea

Asian JOC paper

A synthetic method for accessing chiral α‐alkylthio‐α‐alkylmalonates was successfully established. The enantioselective α‐sulfenylation of α‐alkylmalonates via phase‐transfer catalysis [N‐alkylthiophthalimide, 50% aq. KOH, toluene, −40 °C and N‐2′,3′,4′‐trifluorophenyl‐dihydroquinidium bromide] provided the corresponding α‐alkylthio‐α‐alkylmalonates in high chemical yields (up to 97%) and optical purities (up to 90% ee).

Asian J. Org. Chem. 2019, 8, 1732–1739

DOI10.1002/ajoc.201900346

Enantioselective Synthesis of Chiral α-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed α-Alkylation of α-Acylthiomalonates

Min Woo HaJun Young LeeDoyoung KimGeumwoo LeeJae Kyun LeeSuckchang Hong, and Hyeung-geun Park*

 Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
 Neuro-Medicine Center, Korea Institute of Science and Technology, PO Box 131, Cheongyang, Seoul 130-650, Republic of Korea

jo-2017-02605f_0010

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, −20 °C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding α-acylthio-α-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee).

J. Org. Chem.201883 (2), pp 1011–1018

Enantioselective Synthesis of Chiral α-Azido and α-Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α-Alkylation of α-Bromomalonates, Followed by SN2 Substitution

Doyoung Kim†, Min Woo Ha†, Suckchang Hong‡, Cheonhyoung Park†, Byungsoo Kim†, Jewon Yang†, and Hyeung-geun Park*†

† Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
‡ Korea Research Institute of Chemical Technology, 16 Gajung-ro Yoosung-gu, Daejeon 34114, Korea

jo-2017-003245_0006

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and −40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by SN2 substitution with sodium azide and aryloxides, respectively.

J. Org. Chem., 2017, 82 (9), 4936–4943

A synthetic Nitraria alkaloid, isonitramine protects pancreatic β-cell and attenuates postprandial hyperglycemia

So Jung Kwon a, 1, Su Jung Hwang a, b, 1, Yeonghun Jung a, b, 1, Hyeung-geun Park c, Mi-hyun Kim d, Yohan Park a, b, *, Hyo-Jong Lee a, b, *

a College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 607 Obang-dong, Gimhae, Gyungnam, 621-749, South Korea
b u-Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gyeongnam, South Korea
c Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea
d College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon, 406-799, South Korea

Objective. The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown.
Methods. Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids. In this study, we investigated the anti-diabetic potential of isonitramine in diabetes mellitus and its underlying molecular mechanism in carbohydrate catabolism in vitro and in vivo.
Results. Isonitramine exerted significant inhibitory effect on α-glucosidases but not α-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (STZ)-induced postprandial hyperglycemia and protected the pancreatic damages against alloxan-induced oxidative stress in vivo. Also, isonitramine induced insulin without any toxicities and downregulated phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis.
Conclusion. Taken together, isonitramine inhibited α-glucosidase activity and PEPCK expression, while increased insulin expression, resulting in attenuating the postprandial hyperglycemia. Also, isonitramine protected the pancreas from ROS-mediated toxicities. Therefore, isonitramine may be a new drug candidate for the treatment of diabetes mellitus.

Metabolism, 2017, 70, 107.

http://dx.doi.org/10.1016/j.metabol.2017.02.002

An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent

Su Jung Hwang 1,2, Hyeung-geun Park 3, Yohan Park 1,2,* and Hyo-Jong Lee1,2,*

1 College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, and
2 u-Healthcare and Anti-aging Reearch Center (u-HARC), Inje University, Gimhae, Gyeongnam 621-749;
3 Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea

Previously, we reported that α-quaternary chiral lactam derivatives have broad spectrum anticancer activity. However, the underlying molecular mechanisms and its relevance are largely unknown. In the present study, we report progress on α-quaternary chiral lactam analogues that address this, focusing on the novel analogue YH-304 as a candidate to broadly target human cancer cells. The effect of YH-304 on cell transformation was assessed by clonogenic assay in non-small cell lung cancer cells (NSCLCs) A549 and 226B. Proapoptotic activity of YH-304 was determined by TUNEL assay and cleaved PARP, cleaved caspase-9, and Bax as markers for apoptosis. The p53-dependency and therapeutic spectrum of YH-304 was assessed by western blot analysis, real-time PCR, and cell viability assays in cells expressing endogenous wild or mutant p53. The effect of YH-304 on angiogenesis in vivo was examined by bFGF-mediated angiogenesis assay in zebrafish. Finally, the effect of YH-304 on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of YH-304 on bFGF-mediated angiogenesis was assessed using western blotting. We found that YH-304 significantly decreases the colony-forming activities of both A549 and 226B cells, inducing cellular apoptosis. Unlike nutlin-3 (p53 pathway activator), YH-304 did not affect the expression levels of p53 and its target gene such as p21 and thus showed p53-independent anticancer activity with broad spectrum. In addition, YH-304 inhibited bFGF-induced angiogenesis in vivo through mediating AKT and ERK signaling pathway, which plays an important role in bFGF activation and angiogenesis. Taken together, our data indicate that YH-304 may represent a novel therapeutic option for the treatment of cancer in a p53-independent manner.

Int. J. Oncol. 2016, 49, 2480.

http://dx.doi.org/10.3892/ijo.2016.3726