Semisynthesis of Antitrypanosomal p-Quinone Analog Possesing the Komaroviquinone Pharmacophore.

A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.

Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo.

Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.

Semisynthesis of triptolide analogues: effect of γ-lactone and C-14 substituents on cytotoxic activities.

Triptolide γ-lactone and C-14 analogues were prepared and evaluated cytotoxity against human lung adenocarcinoma epithelial A549 cells and human colon adenocarcinoma HT-29 cells. γ-Lactone substructure and C-14 substituents affected the biological activities significantly.

Fluorination of triptolide and its analogues and their cytotoxicity.

The reaction of triptolide and its analogues with a fluorinating agent, that is, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) or (diethylamino)sulfur trifluoride (DAST), was studied. One of the fluorinated products, 14beta-dehydroxy-14beta-fluoro triptolide, was found to be more cytotoxic than the parent natural triptolide.

Semisynthesis of isetexane diterpenoid analogues and their cytotoxic activity.

Isetexane diterpene analogues were semisynthesized from demethylsalvicanol isolated from Perovskia abrotanoides (Labiatae). The structure and cytotoxic activity relationships (SAR) of the natural parent diterpene, demethylsalvicanol, and its semisynthetic analogues were studied by using P388 murine leukemia cells.

Cytotoxicity of abietane diterpenoids from Perovskia abrotanoides and of their semisynthetic analogues.

Seven known abietane diterpenoids and 11-O- and 12-O-acetylcarnosic acids were isolated from a methanol extract of Perovskia abrotanoides (Labiatae). Structure and cytotoxic activity relationships (SAR) of the natural and semisynthetic analogues of the presently isolated abietane diterpenoids were studied by using P388 murine leukemia cells.

Semisynthesis of C-ring modified triptolide analogues and their cytotoxic activities.

Several C-ring modified analogues of a potent antileukemic diterpene, triptolide (1), were synthesized and their structure-activity relationships were studied.

Inhibitory effects of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), an acyl-CoA:cholesterol O-acyltransferase inhibitor, on cholesterol esterification in the intestine and liver.

The effects of an acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor, N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), on cholesterol esterification in the intestine and liver were investigated in vitro and in vivo. YIC-C8-434 inhibited the formation of cholesteryl [(3)H]oleate from [(3)H]oleic acid and cholesterol both in human colon adenocarcinoma Caco2 cells and in human hepatoma HepG2 cells with IC(50) values of 0.38 and 0.49 microM, respectively. However, it did not influence the incorporation of [(3)H]oleic acid into triacylglycerols and phospholipids. Oral administration of YIC-C8-434 at a dose of 8.3 mg/kg/d inhibited [(14)C]cholesterol absorption by 17% (p<0.01) in rats. YIC-C8-434 also significantly reduced the secretion of very low-density lipoprotein (VLDL) cholesterol from the liver into the plasma at an oral dose of 100 mg/kg/d after an intravenous injection of Triton WR-1339. These results suggest that oral administration of YIC-C8-434 reduces intestinal cholesterol absorption and hepatic VLDL cholesterol secretion by direct inhibition of ACAT in the intestinal epithelium and hepatocytes, respectively. However, the inhibitory action of YIC-C8-434 on cholesterol absorption rather than hepatic cholesterol secretion may play a more important role in its hypocholesterolemic activity, because the effective dose for the former was 12-fold lower than that for the latter.

The metabolic stability of acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors, N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(2, 4-dimethylphenyl)piperazine (YIC-708-424) and its derivatives in rat liver and intestinal epithelium.

The metabolic stability of the acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(2, 4-dimethylphenyl)piperazine (YIC-708-424) and its n-alkoxy derivatives containing an alkyl chain of 3 or 7 to 10 carbons, which exhibited different hypocholesterolemic activities, was investigated in vivo and in vitro in rats. After the oral administration of YIC-708-424 to rats at a dose of 5 mg/kg/d for 7 d, the parent compound was not detected in the blood. On the other hand, when the n-alkoxy derivatives were administered to rats, an increase in the alkyl chain length produced a progressive increase in the blood concentration of the parent compound. Both in the blood of rats administered YIC-708-424 and in the reaction mixture after the incubation of YIC-708-424 with rat hepatic 9000 x g supernatants, an inactive major metabolite, N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(4-carboxyl-2-methylphenyl)piperazine, was observed. The ratio of the maximum velocity to the apparent Michaelis-Menten constant (V(max)/K(m)) for the degradation of the n-propyloxy derivative in rat hepatic and intestinal microsomes was almost equivalent to that of YIC-708-424. On the other hand, an increase in the alkyl chain length of n-alkoxy derivatives produced a progressive decrease in V(max)/K(m) for the degradation of these compounds. Additionally, the in vivo hypocholesterolemic activities of YIC-708-424 and its n-alkoxy derivatives were positively correlated with the blood concentration of the parent compound and were negatively correlated with their V(max)/K(m). These results suggest that the metabolic stability of ACAT inhibitors in the liver and intestinal epithelium, which are the major target organs of these compounds, has a strong influence on their pharmacological activities in vivo.