Jin-Ah Kang

A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells

Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC(50)=1.39 μM) than in DU145 (IC(50)=2.94 μM) and PC3 cells (IC(50)=3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC(50)=1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.

Design, synthesis and anticancer activity of novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives

On the basis of the chemical structures of psorospermin with a xanthone template and acronycine derivatives with an acridone template, rac-1 and rac-2 constructed on an 1,2-dihydrobenzofuro[4,5-b][1,8]naphthyridin-6(11H)-one scaffold were designed and synthesized as potential anticancer agents. Their anticancer activities were evaluated against five human cancer cell lines. Rac-2 showed similar anticancer activity to doxorubicin and rac-1 exhibited even higher anticancer activity against LNCaP (IC(50)=0.14 μM), DU145 (IC(50)=0.15 μM), PC3 (IC(50)=0.30 μM) and MCF-7 (IC(50)=0.26 μM) cancer lines than doxorubicin and rac-2. Also, rac-1 revealed very potent anticancer activity (IC(50)=0.15 μM) against MCF-7/ADR cell (doxorubicin-resistant breast cancer cell) lines and induced G2/M phase arrest of the cell cycle in MCF-7/ADR cells.

Efficient and practical synthesis of l-hamamelose

An efficient synthetic route of L-hamamelose was successfully accomplished starting from D-ribose. L-Hamamelose was synthesized in 42% overall yield with six reaction steps via a stereoselective Grignard reaction, a stereoselective crossed aldol reaction and a controlled oxidative cleavage of the double bond of a vinyl diol compound. During the oxidative cleavage of the double bond of the vinyl diol compound with osmium tetroxide and NaIO(4), an over-oxidative cleavage of alpha-hydroxyl aldehyde generated from ring opening of the first cleaved product, formyl lactol, did not occur, probably due to the stability of the lactol form. A plausible mechanism for the stereoselective crossed aldol reaction was suggested. The final target compound, L-hamamelose can play a very important role as a chiral building block in synthesizing a wide variety of enantiopure compounds.

Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation

Abstract Based upon the fact that l-nucleosides have been generally known to be less cytotoxic than d-counterparts, l-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. d-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, d-thymine nucleoside, d-2 and l-thymine nucleoside, l-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas d-2 exhibited high cytotoxicity in MT-4 cell lines, l-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that l-2 may be a good candidate for an anti-AIDS drug. l-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2′,3′-dideoxy structure. Potent antiviral effects of d-2 and l-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports l-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.

Asymmetric Synthesis of Apio Fluoroneplanocin a Analogs as Potential AdoHcy Hydrolase Inhibitor

Apio fluoroneplanocin A (apio F-NPA, 3) and its uracil analogue 4 have been designed and asymmetrically synthesized starting from D-ribose. Introduction of fluoro group into vinylic position of 5 was accomplished successfully over 5 steps employing key reactions such as iodination according to an addition-elimination reaction mechanism, stereo- and regioselective reduction of α,β -unsaturated ketone, and electrophilic fluorination. This methodology can be adapted to the synthesis of fluoro compounds extensively.

Synthesis of Pyrimidine Analog of Fluoroneplanocin A as Potential Anti- HCV Agent

N-hydroxycytosine nucleoside 3 was synthesized as potential anti-HCV agent, starting from D-ribose using an iodine-fluorine exchange reaction by a help of BuLi, a RCM reaction, a stereoselective reduction and a Mitsunobu reaction as the key steps.

Synthesis of Novel Cyclopropyl Nucleoside Analogues as Potential Antiherpetic Agent

Synthesis of novel cyclopropyl pyrimidine and purine nucleoside derivatives was successfully achieved using one pot reactions including an alkylation, an oxirane-ring opening reaction and a lactonization and a hydroboration-oxidation as the key steps in order to find new antiherpetic agent.