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.

Discovery of 2-((R)-4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

Je Ho Ryu†‡, Jung A Lee†, Shinae Kim†§, Young Ah Shin†, Jewon Yang‡, Hye Young Han†, Hyun Joo Son†, Yong Hyuk Kim†, Joon Ho Sa†, Jae-Sun Kim†∥, Jungeun Lee‡, Jeeyeon Lee‡, and Hyeung-geun Park*‡

† Life Science R&D Center, SK Chemicals, Seongnam-Si, Bundang-Gu, Sampyeong-Dong 686, Gyeonggi-Do 463-400, Korea
‡ Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea


A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound 9. The combination of the replacement of a pyridine ring of 9 with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, 18a (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of 18a significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with 18a.

J. Med. Chem., 2016, 59 (22), 10176–10189.
DOI: 10.1021/acs.jmedchem.6b01122
Publication Date (Web): October 31, 2016
Copyright © 2016 American Chemical Society

Phase-transfer catalyzed enantioselective α-alkylation of α-acyloxymalonates: construction of chiral α-hydroxy quaternary stereogenic centers

Min Woo Ha,a   Sujee Choi,a   Seek Kim,a   Jun Young Lee,a   Jae Kyun Lee,b   Jeeyeon Lee,a   Suckchang Hong*a and   Hyeung-geun Park*a 

The enantioselective synthesis of α-acyloxy-α-alkylmalonates was developed as an efficient method for producing chiral α-tertiary alcohols, which are potentially valuable intermediates in the synthesis of natural products and pharmaceuticals. The efficient enantioselective α-alkylation of diphenylmethyl tert-butyl α-acyloxymalonates was accomplished via phase-transfer catalysis in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide to afford the corresponding α-acyloxy-α-alkylmalonates at high chemical (up to 99%) and optical (up to 93% ee) yields, which could be readily converted to versatile chiral intermediates with a chiral α-tertiary alcohol group.

RSC Adv., 2016, 6, 77427-77430.

DOI:  10.1039/C6RA15121C

*Corresponding authors

a Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea

 b Neuro-Medicine Center, Korea Institute of Science and Technology, PO Box 131, Seoul 130-650, Republic of Korea

Synthesis of Acyclic Selenonucleoside Phosphonates as Potential Antiviral Agents

Pramod K. Sahu, Gyudong Kim, Akshata Nayak, Ji Yoon Ahn, Min Woo Ha, Cheonhyoung Park, Jinha Yu, Hyeung-geun Park, and Lak Shin Jeong*

On the basis of potent antiviral activity of adefovir (1) and tenofovir (2), which are representative acyclic nucleoside phosphonates, bioisosteric acyclic selenonucleoside phosphonates seleno-adefovir (3) and seleno-tenofovir (4) were designed and synthesized from diethyl(iodomethyl) phosphonate (7) by using diselenide chemistry.

Asian J. Org. Chem. 2016, 5, 183 – 186.

Metal-Free α-C(sp3)−H Functionalized Oxidative Cyclization of Tertiary N,N-Diarylamino Alcohols: Construction of N,N-Diarylaminotetrahydropyran Scaffolds

Sualiha Afzal, Arramshetti Venkanna, Hyeung-geun Park, and Mi-hyun Kim*


Herein, we report an efficient synthetic method for the preparation of anomeric N,N-diarylaminotetrahydropyran scaffolds. The free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)/hypervalent iodine(III)- or TEMPO/I2-mediated oxidative cyclization of tertiary amino alcohols was  used to construct N,N-diarylaminotetrahydropyrans through α-C(sp3)-O bond formation, with the loss of only two H atoms. This efficient synthetic method broadens the scope of viable α-C(sp3)-H functionalized amines to include conformational-bias-free substrates.

Asian J. Org. Chem. 2016, 5, 232 – 239.