Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity.

Abstract

Streptomyces amphibiosporus R310-104 (ATCC53964) produced a novel antibiotic lactimidomycin which showed inhibitory activity against fungi and prolonged the survival time of mice transplanted with experimental tumors. Structural studies clarified that lactimidomycin is a new glutarimide antibiotic having a unique unsaturated 12-memberedlactone ring.In the course of screening for new antibiotics effective against experimental tumors, we have isolated a novel antibiotic designated lactimidomycin from the culture broth of Streptomyces amphibiosporus R310-104 collected in Akita city1'2*. The antibiotic exhibited strong cytotoxicity against various tumor cells and inhibitory activity against fungi but no antibacterial activity. It demonstrated prolongation of life span in mice bearing P388 leukemia and B l 6 melanoma. The structure oflactimidomycin was determined by spectroscopic analyses and 13C-enriched biosynthetic studies to be a novel glutarimide group antibiotic having a unique 12-memberedlactone ring as a side chain.In this paper, we describe the production, isolation, physico-chemical properties, structure determination and biological activity of lactimidomycin. Antibiotic Production A loopful mature slant culture of S. amphibiosporus R3 10-104 was inoculated into 100 ml of vegetative mediumconsisting of soluble starch (Nichiden Kagaku) 2%, Pharmamedia(Traders Protein) 1%, ZnSO4-7H2O0.003% and CaCO3 0.4% in a 500-ml Erlenmeyer flask (pH 7.0 before sterilization).The flask was incubated at 32°C for 7 days on a rotary shaker (200rpm) and 5 ml of vegetative inoculum was added to 100ml of sterile production medium containing Protein-S (Ajinomoto Co.) 3%, glucose 3%, Pharmamedia 0.5%, yeast extract (Oriental Yeast Co.) 0.1% and CaCO3 0.3%, pH 7.0 in a 500-ml Erlenmeyer flask. The flask was incubated at 28°C on a rotary shaker (200rpm). Antibiotic production was monitored by the in vitro cytotoxicity against B16 melanomacells and it reached maximumafter 4 days incubation. Isolation and PurificationThe fermentation broth (18 liters, pH 7.4) was stirred with 1-butanol for one hour. The solvent layer was separated from the aqueous layer and mycelial cake by use ofa Sharpies type centrifuge and concentrated under reduced pressure. The residue (30 g) was suspended in water (1 liter) and extracted three times with Lactimidomycin was originally called as BU-4146T or BMY-28886.

iso-Migrastatin, Migrastatin, and Dorrigocin Production in Streptomyces platensis NRRL 18993 Is Governed by a Single Biosynthetic Machinery Featuring an Acyltransferase-less Type I Polyketide Synthase

“…2). Both the 088D and mgs clusters were found to contain genes encoding AT-less type I PKSs, type II acyl carrier proteins (ACPs), and amidotransferases (AMTs) likely associated with biosynthesis of glutarimide-containing polyketides (4,22).…”

“…1) are potent inhibitors of human tumor cell migration and thus represent novel leads for anticancer drug discovery (2)(3)(4)(5). Synthetic analogs of these natural products have also been investigated and found to retain potent activity despite significant structural truncation (6 -8).…”

Isolation and characterization of a new 12-membered macrolide FD-895.

“…The functionalities of the carbon signals of FD-895 were determined by the DEPTspectra. Consistent with its molecular formula, the 13C NMRspectrum of FD-211 gave 13 lines, which were classified into CH3x7, -CH2x4, :CH-x3, OCH3x1, -CHO-x7, :CC Oxl,-CH=x5, X>xl and:C=Ox2. CH3x7, Fig.l.…”

Antiproliferative and antibacterial activity of some glutarimide derivatives

“…They exhibit widespread pharmacological effects, including antitumor [1][2][3][4] , anti-inflammatory 5 , immunomodulatory, antiangiogenic and anxiolytic [6][7][8] . Isolation and examination of pharmacologically active natural glutarimides started in 1960s.…”