Bo Gil Choi

Chemical Modification of Santonin into a Diacetoxy Acetal Form Confers the Ability to Induce Differentiation of Human Promyelocytic Leukemia Cells via the Down-regulation of NF-κB DNA Binding Activity

Many sesquiterpene lactone compounds either induce or enhance the cell differentiation of human leukemia cells. However, we reported in a previous study that santonin, a eudesmanolide sesquiterpene lactone, exerts no effects on the differentiation of leukemia cells. In this report, to evaluate the possibility of chemically modifying santonin into its derivatives with differentiation inducing activity, we synthesized a series of santonin derivatives, and determined their effects on cellular differentiation in the human promyelocytic leukemia HL-60 cell system. A diacetoxy acetal derivative of santonin (DAAS) was found to induce significant HL-60 cell differentiation in a dose-dependent manner, whereas santonin in its original form did not. The HL-60 cells were differentiated into a granulocytic lineage when exposed to DAAS. In addition, the observed induction in cell differentiation closely correlated with the levels of NF-κB DNA binding activity inhibited by DAAS. Both Western blot analyses and kinase inhibitor studies determined that protein kinase C, ERK, and phosphatidylinositol 3-kinase were upstream components of the DAAS-mediated inhibition of NF-κB binding activity in HL-60 leukemia cells. The results of this study indicate that santonin can, indeed, be chemically modified into a derivative with differentiation inducing abilities, and suggest that DAAS might prove useful in the treatment of neoplastic diseases.

SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL EXOMETHYLENE CYCLOPROPYL NUCLEOSIDES

Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feists acid 1 was condensed with purine derivatives by the SN2 type reaction. All the synthesized compounds were evaluated for antiviral activity.

Synthesis and antiviral activity of novel methylene cyclopropyl nucleosides.

Novel exomethylene cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate5 was synthesized in 4 steps, from Feists acid1 and was condensed with purine derivatives by the SN2 type reaction to give some cyclopropyl nucleosides. The synthesized nucleosides did not showed any significant antiviral activity against HSV-1, HSV-2, HCMV, HIV-1, HIV-2, and HBV up to 100 μM.

Synthesis of sesquiterpene derivatives as potential antitumor agents; Elemane derivatives

Derivatives of elema-1,3-diene were synthesized in several steps as polar analogs of β-elemene, antitumor agent under clinical phase. The lactone ring of compound1 was opened by LiAlH4 to give diol2 which was selectively protected by TBDPSCl. After acetylation of the secondary alcohol, the acetylated product was ozonolyzed and reduced to give elemane derivative4 which was converted to diolefin8 via selenides subsequent deprotection by tetrabutylammonium fluoride gave two compounds9, 10.

Induction of human leukemia cell differentiation via PKC/MAPK pathways by arsantin, a sesquiterpene lactone from Artemisia santolina

Abstract Sesquiterpene lactone compounds have received considerable attention in pharmacological research due to their therapeutic effects including anti-cancer and anti-inflammatory activities. In this report, we investigated the effect of arsantin, a sesquiterpene lactone compound present in Artemisia santolina, on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Arsantin significantly induced HL-60 cell differentiation in a concentration-dependent manner. Cytofluorometric analysis indicated that arsantin induced HL-60 cell differentiation predominantly into granulocytes. Both PKC and MAPK inhibitors suppressed the HL-60 cell differentiation induced by arsantin. Moreover, treatment with arsantin increased protein levels of PKCα and PKCβII isoforms, and also induced increased protein levels and phosphorylation form of MAPKs in HL-60 cells. Importantly, arsantin synergistically enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-(OH)2D3 or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)2D3 or ATRA by arsantin may improve outcomes in the therapy of acute promyelocytic leukemia.

Studies on the synthesis andin vitro antitumor activity of the isoquinolone derivatives

Abstract3-Arylisoquinolin-1(2H)-ones (2) are possible bioisosteres of the 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a]isoquinoline (1) which is in clinical evaluation for the treatment of cancer. Structure-activity relationship studies of 3-arylisoquinolin-1(2H)-ones (2) led to the synthesis of 3-arylquinolin-2(1H)-ones (3). A number of 3-phenyl substituted quinolin-2(1H)-ones were synthesized and tested for theirin vitro antitumor activity against four different human tumor cell lines and 3-phenyl-N-benzyl-3,4-dihydroquinolin-2(1H)-one (12) showed the most potent activity.

Synthesis of DAAS derivatives and their enhancement of HL-60 leukemia cell differentiation

DAAS is the diacetoxy acetal derivative of a-santonin and induces HL-60 cell differentiation into granulocytes. In this report, we investigated the structure-activity relationship (SAR) of DAAS derivatives in the differentiation of human HL-60 leukemia cells. Although its derivatives themselves had less effect on HL-60 cell differentiation than DAAS, the monoacetyl derivative, 2, mainly induced HL-60 cell differentiation. Moreover, compound 2 synergistically enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation when combined with 50 nM ATRA, a well-known differentiation inducer. This enhancing effect is similar to that of DAAS in ATRA-induced differentiation.

Synthesis of diacetoxy acetal derivatives of santonin and their enhancing effects on HL-60 leukemia cell differentiation.

Several diacetoxy acetal analogues have been synthesized from santonin and assessed for their ability of inducing or enhancing the differentiation of human HL-60 leukemia cells. The compounds themselves had little effect on HL-60 cell differentiation. However, three analogues,2a, 3a, and5b, synergistically enhanced 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced HL-60 cell differentiation when combined with 5 nM of dihydroxyvitamin D3 [1,25-(OH)2D3], a well-known differentiation inducer. Especially, the compound5b profoundly enhanced the 1,25-(OH)2D3]-induced HL-60 cell differentiation.

Synthesis and antiviral activity of novelc-methyl branched cyclopropyl nucleosides

A series of novel cyclopropyl nucleosides was synthesized using the highly stereoselective Simmons-Smith reaction starting from 1,2:5,6-di-O-isopropylidene-D-mannitol. The structural assignments of these nucleosides were determined by NMR studies and X-ray crystallography. All the synthesized nucleosides were assayed against several viruses.

Stability of antineoplaston A10 in aqueous solution

The analysis method and stability test of antineoplaston A10, a new anticancer drug candidate, were established. A10 and phenylacetyl- L-glutamine, one of the degradation products, can be detected by high-performance liquid chromatography. The degradation kinetics of antineoplaston A10 in aqueous solutions from pH 1 to 10 buffers were carried out at 40, 50 and 60°C. Pseudo-first order kinetics were obtained throughout the entire pH ranges studied. The pH-rate profiles showed that antineoplaston A10 was very unstable in alkaline conditions and most stable at pH4.