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21-deoxymacbecin analogues useful as antitumor agents

A technology of deoxymacbecin and macbecin, applied in the direction of antineoplastic drugs, resistance to vector-borne diseases, drug combinations, etc.

Inactive Publication Date: 2009-01-14
BIOTICA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Although many of these derivatives exhibit reduced hepatotoxicity, they still have very limited water solubility

Method used

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  • 21-deoxymacbecin analogues useful as antitumor agents
  • 21-deoxymacbecin analogues useful as antitumor agents
  • 21-deoxymacbecin analogues useful as antitumor agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Example 1 - Sequencing of the macbecin biosynthetic gene cluster

[0211] Genomic DNA was isolated from A. amaranthus (ATCC 31280) and A. miraculous (DSM 43827, ATCC 29888) using the standard protocol described in Kieser et al. (2000). DNA sequencing was carried out using standard methods at the Sequencing Facility at the University of Cambridge's Department of Biochemistry, Tennis Court Road, Cambridge CB21QW.

[0212] Using primers BIOSG1045'-GGTCTAGAGGTCAGTGCCCCCGCGTACCGTCGT-3' (SEQ ID NO: 7) and BIOSG1055'-GGCATATGCTTGTGCTCGGGCTCAAC-3' (SEQ ID NO: 8), amplified from Streptomyces hygroscopicus NRRL 3602 (sequence accession number: AY179507) using standard techniques The carbamoyltransferase-encoding gene gdmN in the geldanamycin biosynthesis gene cluster. Southern blot experiments were performed according to the manufacturer's instructions (Roche) using DIG reagent and a kit for non-radioactive nucleic acid labeling and detection. DIG-labeled gdmN DNA fragments wer...

Embodiment 2

[0220] Example 2 - Production of Strain BIOT-3806: An Actinomyces acarina in which the gdmM homologue mcbM has been disrupted by inserting a plasmid

[0221] A summary of the construction of pLSS308 is at image 3 displayed in .

[0222] 2.1. Construction of plasmid pLSS308

[0223] DNA sequences of the gdmM gene from the geldanamycin biosynthesis gene cluster of Streptomyces hygroscopicus strain NRRL 3602 (AY179507) and orf19 from the rifamycin biosynthesis gene cluster of Amycolatopsis mediterranei (AF040570AF040571) Sequences were aligned using the VectorNTI sequence alignment program (Figure 4). This alignment identifies regions of homology suitable for the design of degenerate oligomers used to amplify DNA from Actinomyces fasciculatus (BIOT-3134; DSM43827; ATCC29888). Fragments of homologous genes. The degenerate oligomers are:

[0224] FPLS1: 5': ccscgggcgnycngsttcgacngygag 3'; (SEQ ID NO: 18)

[0225] FPLS3: 5': cgtcncggannccggagcacatgccctg 3'; (SEQ ID NO: 19) ...

Embodiment 3

[0237] Example 3 - Generation and isolation of new compounds

[0238] 3.1 Fermentation and isolation of 7-O-carbamoyl promacbecin

[0239] Nutrient stock solutions of BIOT-3806 were prepared after growth in Medium 1 containing 50 mg / L ampramycin and stored in distilled water with 20% w / v glycerol: 10% w / v lactose and at -80°C storage. Nutrient stocks were recovered on ISP2 medium (medium 3) plates supplemented with 50 mg / L ampramycin and incubated at 28°C for 48 hours. Vegetative cultures were obtained by removing two 5 mm diameter agar pieces from the ISP2 plate and inoculating them into 30 mL of Medium 1 containing 50 mg / L ampramycin in a 250 mL shake flask. The flasks were incubated at 28°C for 48 hours at 200 rpm (5 cm stroke).

[0240] The vegetative culture was inoculated at 5% v / v into 200 mL of production medium (Medium 2) in 2L shake flasks. Culturing was performed at 300 rpm (2.5 cm stroke) at 28°C for 1 day followed by 5 days at 26°C.

[0241] The fermentatio...

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Abstract

The present invention relates to 21-deoxymacbecin analogues that are useful, e.g. in the treatment of cancer, B-cell malignancies, malaria, fungal infection, diseases of the central nervous system and neurodegenerative diseases, diseases dependent on angiogenesis, autoimmune diseases or as a prophylactic pretreatment for cancer. The present invention also provides methods for the production of these compounds and their use in medicine, in particular in the treatment and / or prophylaxis of cancer or B-cell malignancies.

Description

Background of the invention [0001] The 90 kDa heat shock protein (Hsp90) is an abundant chaperone involved in protein folding and assembly, many of which are involved in signal transduction pathways (for review see Neckers, 2002; Sreedhar et al., 2004a; Wegele et al., 2004 and references therein). Nearly 50 of these so-called client proteins have been identified to date and include steroid receptors, non-receptor tyrosine kinases such as the src family, cyclin-dependent kinases such as cdk4 and cdk6, cystic fibrosis transmembrane regulators (cystic transmembrane regulator), nitric oxide synthase and others (Donze and Picard, 1999; McLaughlin et al., 2002; Chiosis et al., 2004; Wegele et al., 2004; http: / / www.picard.ch / downloads / Hsp90interactors.pdf ). Furthermore, Hsp90 plays an important role in the stress response and in protecting cells against mutations (Bagatell and Whitesell, 2004; Chiosis et al., 2004). The function of Hsp90 is complex and it is involved in the format...

Claims

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Application Information

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IPC IPC(8): C07D225/06A61K31/395A61P35/00
CPCY02A50/30
Inventor C·J·马丁B·威尔金森S·盖瑟M-Q·张R·M·谢里登L·S·希恩R·E·莱尔M·努尔阿拉姆W·A·沃斯登
Owner BIOTICA TECH
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