ABSTRACT
New derivatives of spicamycin modified at the fatty acid moieties of the molecule were synthesized and their structure-activity relationships were examined. The antitumor activity was greatly influenced by modification of the fatty acid moieties to tetradecadienoyl or dodecadienoyl analogues exhibiting better antitumor activity against COL-1 human colon cancer xenograft than SPM VIII.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Animals , Antibiotics, Antineoplastic/biosynthesis , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Neoplasm Transplantation , Purine Nucleosides/biosynthesis , Purine Nucleosides/chemistry , Purine Nucleosides/pharmacology , Streptomyces/metabolism , Structure-Activity RelationshipABSTRACT
A series of SPM VIII analogs were synthesized to investigate the effect of the amino acid moiety on the antitumor activity. The L-threonine analog and the glycylglycine analog of SPM VIII showed much higher cytotoxicity to P388 murine leukemia cells (IC50 5.8 nM and 0.11 nM, respectively) than SPM VIII (IC50 25nM). However, replacement of the glycine moiety with other amino acids greatly reduced the antitumor activity against COL-1 human colon cancer xenograft model. This study indicated that the glycine moiety of SPM VIII is crucial for the antitumor effect.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Amino Acids/pharmacology , Animals , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/therapeutic use , Colonic Neoplasms/drug therapy , Female , Humans , Leukemia P388/drug therapy , Mice , Mice, Nude , Molecular Structure , Neoplasm Transplantation , Purine Nucleosides/therapeutic use , Structure-Activity RelationshipABSTRACT
The antitumor activity of spicamycin analogue SPM VIII against human stomach, breast, lung, colon and esophageal cancers was compared to that of mitomycin C (MMC) in the human tumor-nude mice xenograft model. Comparative studies of SPM VIII given i.v. at 6 mg/kg/day daily for 5 days and MMC given i.v. at 6.7 mg/kg on day 1 revealed that the antitumor spectrum of SPM VIII showed a different pattern from that of MMC and that SPM VIII caused tumor mass reductions in more tumors than did MMC in colon cancers (4/12 versus 1/11). In addition to this study, a comparative study of SPM VIII given i.v. at 12 mg/kg/day 8 times at 3- or 4-day intervals and 5'-deoxy-5-fluorouridine (5'-DFUR) given po at 185 mg/kg/day 5 days per week for 4 weeks showed that SPM VIII had the highest effect on SC-9 human stomach cancer and COL-1 human colon cancer among the 3 compounds, resulting in a significant reduction of tumor mass. Although other pharmacological studies are in progress, these results suggest that SPM VIII might be a novel antitumor compound effective for human cancers including cancer of the digestive organs.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Neoplasms, Experimental/drug therapy , Animals , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitomycin/therapeutic use , Neoplasm Transplantation , Purine Nucleosides/therapeutic use , Transplantation, HeterologousSubject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/isolation & purification , Chemical Phenomena , Chemistry, Physical , Ethers/chemistry , Ethers/isolation & purification , Ethers/pharmacology , Furans/chemistry , Furans/isolation & purification , Furans/pharmacology , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Mass Spectrometry , Phosphatidylinositols/metabolism , Streptomyces/chemistry , Streptomyces/metabolismABSTRACT
Thiazohalostatin has been isolated from the culture broth of Actinomadura sp. by a screening program designed to find novel cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as colorless powder. Thiazohalostatin prevented cell death caused by calcium overload and exhibited an inhibitory activity against lipid peroxidation.
Subject(s)
Actinomycetaceae/chemistry , Lipid Peroxidation/drug effects , Pyrroles/isolation & purification , Thiazoles/isolation & purification , Animals , Cell Death/drug effects , Down-Regulation , Fermentation , Mice , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Spicamycin, a nucleoside antibiotic containing fatty acids with a variety of chain lengths (C12-C18), showed potent antitumor activity against human gastric cancer SC-9 and human breast cancer MX-1 in a xenograft model. We have made several semi-synthetic spicamycin analogues (SPMs) which differed in the chain length of the fatty acid moiety, and examined their structure-antitumor activity relationship. The cytotoxic activities of SPMs depended on the chain length of the fatty acid moiety, with dodecanoyl, tetradecanoyl, hexadecanoyl and icosanoyl analogues (SPM VIII, SPM X, SPM XII and SPM XVI) exhibiting the most potent cytotoxic activity against P388 murine leukemia cells. SPM VIII showed the most activity against SC-9 in the human tumor xenograft model with the highest therapeutic index among SPMs. The antitumor activity of SPM VIII was superior to that of mitomycin C.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Animals , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Humans , Leukemia P388/drug therapy , Leukemia P388/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasm Transplantation , Purine Nucleosides/chemistry , Purine Nucleosides/pharmacology , Purine Nucleosides/therapeutic use , Stomach Neoplasms/drug therapy , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A new antitumor antibiotic vicenistatin was isolated from the culture broth of Streptomyces sp. HC34. The structure of vicenistatin was elucidated by NMR spectral analysis. Vicenistatin exhibited antitumor activity against human colon carcinoma Co-3 in the xenograft model.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Lactams , Macrolides , Animals , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Antibiotics, Antineoplastic/biosynthesis , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/isolation & purification , Drug Screening Assays, Antitumor , Fermentation , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Molecular Structure , Streptomyces/classification , Streptomyces/metabolism , Tumor Cells, CulturedABSTRACT
Rumbrin has been isolated from a fungus, Auxarthron umbrinum, by a screening program designed to find microorganism-produced cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as fine red needles. Rumbrin prevented cell death caused by calcium overload and exhibited a potent inhibitory activity against lipid peroxidation.
Subject(s)
Calcium Channel Blockers/isolation & purification , Fungi/chemistry , Lipid Peroxidation/drug effects , Pyrones/isolation & purification , Pyrroles/isolation & purification , Animals , Calcium Channel Blockers/pharmacology , Cell Line , Fermentation , Mice , Pyrones/pharmacology , Pyrroles/pharmacology , RatsABSTRACT
Pyrrolostatin, a new lipid peroxidation inhibitor, was isolated from the culture of Streptomyces chrestomyceticus EC40. The structure was determined to be 4-geranylpyrrole-2-carboxylic acid on the basis of its spectroscopic and physico-chemical properties. Pyrrolostatin inhibited lipid peroxidation in rat brain homogenate.