Synthesis and antitumor activity of 4'-O-acylanthracyclines.

4'-O-Acyl derivatives of doxorubicin, daunorubicin, 13-deoxocarminomycin, 13-deoxo-10-hydroxycarminomycin, 13-deoxo-11-deoxycarminomycin were synthesized through the formation and mild acid hydrolysis of 2-oxazoline intermediates. The antitumor activity of these 4'-O-acyl derivatives against P388 leukemia was similar to or more effective than the parent anthracyclines.

Synthesis and anti-inflammatory activity of antioxidants, 4-alkylthio-o-anisidine derivatives.

In order to search for anti-inflammatory agents against autoimmune diseases, we synthesized 4-alkylthio-o-anisidine derivatives possessing antioxidant activity, and tested them for anti-inflammatory activity against the Arthus reaction in mice. Experimental inflammations, including the Arthus reaction, concanavalin A, phorbol ester and pyrophosphate-induced edemas in rats were inhibited by 4-propylthio-o-anisidine, which inhibited autoxidation of rat brain homogenate and suppressed the lipopolysaccharide-induced increase in the plasma malondialdehyde level in mice. An antioxidant may be an effective agent in immune complex type inflammation where active oxygen species play an important role.

Absolute structure-cytotoxic activity relationships of steganacin congeners and analogues.

The cytotoxic activities of optically pure and racemic steganacin congeners and analogues against KB cells in culture and the inhibitor activity of cilia regeneration in Tetrahymena were studied with regard to absolute and relative configurations. The stereochemical requirements of dibenzocyclooctadiene lignan lactones for activity were clarified.

Cellular pharmacology of MX2, a new morpholino anthracycline, in human pleiotropic drug-resistant cells.

We previously reported that MX2, a new morpholino anthracycline, showed marked effects on pleiotropic drug-resistant sublines of murine P388 leukemia in vivo as well as in vitro. In this study we examine the in vitro cytotoxicity against pleiotropic drug-resistant sublines of human tumor cell lines. MX2 was effective against multidrug-resistant sublines of four human tumor cell lines; these cells, having a 4.8- to 200-fold cross-resistance to Adriamycin (ADM) showed only a 0.7- to 2.3-fold resistance to MX2 compared with the sensitive cells. To elucidate the mechanism by which MX2 overcomes multidrug resistance, the intracellular pharmacology of MX2 in human myelogenous leukemia K562 and its ADM-resistant subline (K562/ADM) was examined. Both K562 and K562/ADM cells accumulated MX2 more easily than ADM, and the intracellular accumulation of MX2 attained a steady state in both cell lines within 30 min of incubation at 37 degrees C. The amount of MX2 that accumulated in K562/ADM at a steady state was only 1.3 times lower than that in K562. However, ADM was accumulated slowly in both cell lines compared with MX2, and the intercellular concentration reached a steady state in K562/ADM after 90 min of incubation and in K562 after more than 120 min. K562/ADM cells accumulated a 3.3-fold lower concentration of ADM than K562 after 120 min of exposure. The steady-state concentration of ADM in K562/ADM was 8.3 times lower than that of MX2. In addition, greater than 70% of MX2 was retained in both cell lines after 150 min of incubation in the absence of this drug. Verapamil, a calcium antagonist, hardly augmented the cytotoxicity of MX2 against K562/ADM, and no distinct effect of this drug on both the time course and the maximal level of accumulation of MX2 was observed. Interestingly, MX2 effectively inhibited ATP/Mg2(+)-dependent [3H]vincristine binding to K562/ADM membrane preparations, indicating that MX2 could be transported outside the cell by an active efflux pump. The high intracellular accumulation and retention of MX2 in K562/ADM through the rapid influx of the drug into the cells may be one of the reasons why MX2 circumvents pleiotropic drug resistance.

Role of DNA-binding in the cytotoxicity of an anthracycline, R20X2 and its morpholino analog, MX2.

3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), a morpholino anthracycline derived from 13-deoxo-10-hydroxycarminomycin (R20X2) was 16 times less cytotoxic than R20X2 against cultured P388 leukemia cells. The reduced cytotoxicity of MX2 was not explainable by intracellular or intranuclear concentration of the drug or by its DNA-intercalating activity. Binding of MX2 and R20X2 to DNA was measured, after isolating the DNA fraction from an incubation mixture of the drugs with P388 cells or with calf thymus DNA. The amount of R20X2 bound to the DNA was obviously larger than that of MX2, and was dependent on incubation time. These data suggest that the poor binding activity of MX2 to DNA contributes to its reduced cytotoxicity.

MX2, a morpholino anthracycline, as a new antitumor agent against drug-sensitive and multidrug-resistant human and murine tumor cells.

MX2, a new morpholino anthracycline, showed similar or superior chemotherapeutic effects to Adriamycin (ADM) against several experimental murine tumors. i.v. administration of MX2 against L1210-bearing mice induced a prolongation of life-span by twice or more compared to ADM. MX2 was equally or slightly more effective against Lewis lung carcinoma and colon adenocarcinomas 26 and 38 than ADM when either drug was given i.v. The antitumor activity of MX2 against human tumor xenografts was similar to that of ADM, and the compound was effective against three out of four gastric adenocarcinomas, one out of two non-small-cell lung carcinomas, and two out of two mammary adenocarcinomas. In particular, this compound exhibited a marked effect against MX-1, a human mammary adenocarcinoma. MX2, in contrast to ADM, was effective against sublines of P388 leukemia resistant to ADM or aclacinomycin A in vivo as well as in vitro. A maximum percentage increase in life-span of about 90% was obtained in mice bearing these resistant tumors. MX2 is a unique anthracycline antibiotic effective on drug-sensitive as well as multidrug-resistant murine and human cells.

[Effect of MX-2, a morpholino anthracycline derivative, against human and rat glioma cells and experimental leptomeningeal tumors in rats].

MX-2, a new morpholino anthracycline derivative, showed broad anti-neoplastic activity against experimental tumors. Molecular weight of MX-2 is 622.07, and it can cross blood-brain barrier because of its high lipid solubility. In this report, we described its in vitro and in vivo effects on brain tumors. The growth of rat 9L and human KNS-42 glioma cells were markedly inhibited by the medium containing more than 1 ng/ml of MX-2. The inhibitory concentration of MX-2 for 50% cell kill was 1.8 ng/ml for 9L cell and 18 ng/ml for KNS-42, respectively. These values were the almost same as those reported with P388 leukemia. In rats with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, the median survival time was significantly prolonged. The increased life span was 40, 40, 40 (p less than 0.01), and 20% (p less than 0.05) in the animals given intravenous MX-2 of 1.5, 1.0, 0.75, and 0.375 mg/kg on day 1, 5, and 9 after tumor inoculation respectively. These results indicate that MX-2 may be a promising new antineoplastic agent for the treatment of malignant brain tumor.

Antitumor activity of new morpholino anthracyclines.

Antitumor activity of 3'-deamino-3'-morpholino anthracyclines was examined. Morpholino derivatives of 13-deoxocarminomycins, MX2 (1), MX (2) and MY5 (3) shown in Fig. 1, administered iv showed increase in life span (ILS) values over 110% against ip-inoculated P388 leukemia. The ranges of effective doses of these compounds were broader than those of their parent drugs. The morpholino derivatives of doxorubicin and carminomycin, however, were not so effective as their parent drugs. Among these compounds, MX2 administered orally showed nearly the same effects as those obtained by iv administration against P388 leukemia. MX2 administered iv showed 89% ILS against intracerebrally-inoculated L1210 leukemia. The highly lipophilic nature of MX2 could contribute partly to achieving chemotherapeutic responses against intracerebrally-inoculated tumors or by oral administration.

Arugomycin, a new anthracycline antibiotic. III. Biological activities of arugomycin and its analogues obtained by chemical degradation and modification.

Biological activities of arugomycin and its analogues obtained by chemical degradation and modification were evaluated. Differences in the sugar moieties affected their biological activities including induction of differentiation of mouse Friend erythroleukemia cells and mouse myeloid leukemia cells, antitumor activities against sarcoma S-180, Ehrlich ascites carcinoma and P388 leukemia, and cytotoxicity against murine leukemia cells. Some relationships were found between the sugar moieties and biological activities.

A proposed method for exploring anti-aggregatory effects of eicosapentaenoic acid in the rat.

Eicosapentaenoic acid (EPA) has been reported to be anti-aggregatory in humans, but it is difficult to confirm that anti-aggregatory effect in rat. To induce an anti-aggregatory effect of EPA even in rats, an attempt was made to modify fatty acid composition of the diet, i.e., a diet low in linoleic acid, which is a precursor of arachidonic acid (AA) in vivo. A group of rats eating EPA with butter, which contained low linoleic acid, as a lipid source for 12 consecutive days revealed significant inhibition of platelet aggregation induced by collagen. The inhibition was complete at 3.0 micrograms of collagen, a dose which caused complete aggregation in rats which received EPA with corn oil. In these experiments, the ratio of EPA to AA in platelet phospholipids was 0.038 for corn oil, 0.306 for corn oil plus EPA, 0.050 for butter and 0.703 for butter plus EPA. These results indicated that if one blocks the in vivo supply of AA, it causes an increase in EPA to AA ratio in platelet phospholipids, and consequently leads to an inhibition of platelet aggregation even in the rat.