quinocarcin and Leukemia-P388

O-Demethyl-DX-52-1 (3a) was prepared from quinocarcin (1) in two steps (cyanation and O-demethylation). Upon treatment with Fremy's salt, 3a and its esters 3b, 3c afforded the desired quinone 4-6 in good yields. Various substituted quinones 12-37, 47-50 were prepared from 4-6 by Thiele acetylation followed by hydrolysis of acetates and halogenation, by direct addition of amine, alcohol and mercaptan, and by epoxidation and subsequent opening of the epoxide ring with aniline. The quinonemonoketals 39b and 40 were obtained from the corresponding methoxyphenols 7b and 38b. Addition of hydroxylamine gave the quinoneoxime 44 regiospecifically. The antitumor activity of the bis-methylthioquinone (37) among the various derivatives was the most promising.

Topics: Animals; Antibiotics, Antineoplastic; Isoquinolines; Leukemia P388; Mice; Mice, Inbred Strains; Quinones; Tumor Cells, Cultured

Cyanation of quinocarcin readily opened the oxazolidine ring to provide DX-52-1 (2), which was a key compound in the synthesis of quinocarcin derivatives. Various electrophilic reactions toward aromatic ring of DX-52-1 were examined, and 10-substituted (e.g., halogen, nitro, formyl, cyano, hydroxy, etc.) analogs were prepared. Dehydrocyanation of the derivatives could be achieved to reproduce the oxazolidine ring upon treatment with HCl or AgNO3. 10-Chloride 10 and 10-bromide 11 were the most promising among the derivatives prepared. Antitumor activity of 10 was extended to B-16 melanoma.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry; Isoquinolines; Leukemia P388; Mice; Mice, Inbred BALB C; Mice, Inbred Strains

A novel antitumor antibiotic, 2a,3,4,5,6,6a,7,11b-octahydro-11-methoxy-12-methyl-3,6-imino-1H-2-oxa-11 c- azanaphth(1,2,3-cd)azulene-5-carboxylic acid monocitrate (quinocarmycin citrate; KW2152) was selected for investigation in a number of experimental tumor systems because of its efficacy against P388 leukemia. In the initial studies with P388 leukemia (i.p.-i.p.), KW2152 gave an increase in life span of greater than 80%. The activity was schedule dependent and daily administration was the most effective. KW2152 caused marginal activity against L1210 leukemia, B16 melanoma, and M5076 sarcoma. The effect on cultured cells suggested that KW2152 was not cross-resistant to Adriamycin (ADM) but was cross-resistant to mitomycin C (MMC); however, KW2152 caused prolongation of life span against mice bearing P388/ADM or P388/MMC. In tests against human tumors xenografted s.c. in nude mice, KW2152 significantly inhibited the growth of MX-1 mammary carcinoma with all tumors cured at i.v. doses of 4.4 mg/kg/day and p.o. doses of 26.2 mg/kg/day given daily for 7 days. KW2152 also inhibited distinct human gastric carcinomas, St-4 and St-15 tumors, and colon carcinoma Co-3 by daily administration for 7 days. Against St-4, KW2152 gave a treated versus control percentage of 27, compared to 52 for cis-diamminedichloroplatinum. Against Co-3, KW2152 was at least as effective as MMC, ADM, cis-diamminedichloroplatinum, and bleomycin, giving a treated versus control percentage of 18 at a dose of 8.6 mg/kg/day given daily for 7 days. KW2152 showed growth inhibitory activity against cultured murine tumors and human cells. The order of in vitro efficacy of KW2152 against murine tumors, P388 leukemia greater than L1210 leukemia, B16 melanoma, correlated with the order of the sensitivity on the i.p.-i.p. systems of these tumors. The 50% inhibitory concentrations against P388 leukemia cells were 5.3 X 10(-6) and 1.1 X 10(-7) M after 1 and 72 h exposure, respectively. KW2152 caused significant inhibition of RNA synthesis after a short time exposure. In P388 leukemia cells exposed for 1 h with KW2152, the 50% inhibitory concentration for RNA synthesis was 10(-5) M, 30-fold less than that for DNA synthesis. White blood cell depression or platelet depression was not significant after administration of the i.v. 10% lethal dose given daily for 7 days. Because of its good activity against human mammary tumor MX-1 and some effectiveness against other gastric and colon carcinomas and its wa

Topics: Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Line; Cisplatin; DNA; Dose-Response Relationship, Drug; Humans; Isoquinolines; Leukemia P388; Male; Mice; Mice, Inbred Strains; Mitomycin; Mitomycins; Neoplasms, Experimental; Protein Biosynthesis; RNA; Stomach Neoplasms

A novel antitumor antibiotic, DC-52 was found in the culture broths of Actinomycete DO-52. The producing organism was subsequently determined to be a new species and named Streptomyces melanovinaceus nov. sp. For the production of the antibiotic, soluble starch served as a good carbon source and soybean meal was a good nitrogen source tested. The antibiotic DC-52 is active against Bacillus subtilis, Staphylococcus aureus and Klebsiella pneumoniae, but not active against most Gram-negative bacteria. The antibiotic is also active against mouse leukemia P388.

Topics: Animals; Antibiotics, Antineoplastic; Bacteria; Fermentation; Isoquinolines; Leukemia P388; Mice; Streptomyces