Yong-Baik Cho

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R-4, 5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO HI (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 205 3R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.

Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid derivatives in rat hepatic stellate cell-line, HSC-T6.

The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 μM to over 2000 μM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to N=C and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase α and β subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.

Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R )-4,5-bis(aminomethyl)-2-isopropyl- 1, 3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics

The pharmacokinetics and ex vivo pharmacodynamics studies oncis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0→∞) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 μg h ml−1 (mean ± SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min−1 kg−1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P<0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

A Phase I study of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies

A Phase I study of cis‐malonato[(4R,5R)‐4,5‐bis(aminomethyl)‐1,3‐dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies.

Neuroprotective effects of INM-176 against lipopolysaccharide-induced neuronal injury.

Neuroinflammation plays a critical role in the etiology of chronic neurodegenerative diseases such as Alzheimers disease. INM-176 is a standardized ethanolic extract of Angelica gigas, which has been traditionally used as a tonic to treat anemia. In the present study, we investigated whether INM-176 exhibits neuroprotective activities against lipopolysaccharide (LPS)-induced neuronal damage in vitro and in vivo. In primary microglial cells, INM-176 significantly inhibited LPS-induced nitric oxide release and expression of tumor necrosis factor-α and interleukin-1β. The expression levels of inducible nitric oxide synthase and cylcooxygenase-2 in BV2 microglial cells were markedly upregulated by LPS, but this increased expression was counteracted by INM-176. LPS-mediated neuronal damage in an organotypic hippocampal slice culture was also attenuated by the administration of INM-176. In addition, LPS (1 μg/2 μl, i.c.v.)-induced cognitive dysfunction in mice, as determined by passive avoidance and Y-maze tasks, was significantly attenuated by the administration of INM-176. Furthermore, the activation of microglia or astrocytes by LPS in the hippocampal regions of mice was suppressed by INM-176. These results suggest that the neuroprotective and cognition ameliorating effects of INM-176 against LPS-induced damage are mediated, in part, by its anti-inflammatory activities.

Synthesis and evaluation of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1- yl)purines as potential prodrugs of penciclovir.

A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purin es (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut -1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH.H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86 94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9 12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time ( > 21, 13+/-5.0 (SEM), and 13+/-1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment.

Synthesis and evaluation of amino acid ester prodrugs of penciclovir

The synthesis, aqueous solubility and stability, in vitro antiviral activity, and oral bioavailability of the amino acid ester prodrugs of penciclovir, 13–20, 23, and 24, are described. All of the prodrugs were highly soluble (>100 mg/mL) and sufficiently stable in aqueous solution. The oral bioavailability of O-acetyl-O-l-valylpenciclovir (13) (34 %) in mice was comparable to that of famciclovir (33 %) and approximately 4-fold higher than that of penciclovir.

Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis - malonato[(4R, 5R )-4,5-bis(aminomethyl)- 2-isopropyl-1,3-dioxolane]platinum(II)

Abstract The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato- [(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C × T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C × T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10 ± 0.49 (mean ± SD), 1.24 ± 0.06, 0.43 ± 0.07, and 0.25 ± 0.04 μg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1–3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

Synthesis and antitumor activity of (2R,3R)-2,3-dihydroxy- and -2,3-dialkoxy-1,4-diaminobutane platinum(II) complexes

Abstract The synthesis and antitumor activity of (2R,3R)-2,3-dihydroxy- and -2,3-dialkoxy-1,4-diaminobutane platinum(II) complexes 10–15 are described. cis-Dichloro[(2R,3R)-2,3-dimethoxy-1,4-diaminobutane]platinum(II) (bd11) and cis-(cyclobutane01,1-dicarboxylato)[(2R,3R)-2,3-dihydroxy-1,4-diaminobutane]platinum(II) (bd13) showed the potent antitumor activity against L1210 leukemia in mice with % T/C values of around 200.

Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Potassium Channel Opener, SKP-450, in Healthy Volunteers

To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP‐450, a novel K+ channel opener, a single blind, randomized, placebo‐controlled, dose‐rising, parallel‐group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 μg, 100 μg, 200 μg, and 300 μg. Single doses of SKP‐450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 μg group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP‐450 and SKP‐818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose‐related pharmacological effects were obvious for both the 200 μg and 300 μg groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose‐dependent changes. The area under the time‐effect curve (AUEC) of the parameters also showed a similar dose‐dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 μg group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP‐450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP‐450 needs to be evaluated in hypertensive patients after multiple dosing.