NEW CYTOTOXIC CYCLOPEPTIDE AND ITS USE FOR THE TREATMENT OF CANCER
Patent number: WO2004012756
Publication date: 2004-02-12
Inventor: TRUJILLO MARTA (ES); LUNA MARIA JESUS (ES); FERNANDEZ-PUENTES JOSE LUIS (ES); CASTRO JULIAN (ES); CANEDO LIBRADA MARIA (ES); GARCIA GRAVALOS DOLORES (ES)
Applicant: INST BIOMAR SA (ES); TRUJILLO MARTA (ES); LUNA MARIA JESUS (ES); FERNANDEZ-PUENTES JOSE LUIS (ES); CASTRO JULIAN (ES); CANEDO LIBRADA MARIA (ES); GARCIA GRAVALOS DOLORES (ES); RUFFLES GRAHAM KEITH (GB)
Classification:
- international: C07K5/103; C07K11/02; C12P21/02; A61K38/00; C07K5/00; C07K11/00; C12P21/02; A61K38/00; (IPC1-7): A61K38/12; A61P35/00; C07K7/56; C12N1/14
- european: C07K5/10A1B; C07K11/02; C12P21/02; C12R1/645
Application number: WO2003GB03433 20030806
Priority number(s): GB20020018272 20020806; GB20020021696 20020918
Abstract of WO2004012756
A compound is provided with a cyclopeptide structure of formula (1) (IB01212) or pharmaceutically acceptable salts, derivatives, prodrugs or steroisomers thereof: the compound can be obtained by cultivating a microorganism such as the culture strain ESNA-A009, available under accession number CECT 20477, from the Collección Espaola de Cultivos Tipo at the University of Valencia, Spain.
Se presento de manera ofial en el : "" 19 APS Symposium el 18 de Junio del 2005 en S.Diego , California "" :
http://www.americanpeptidesociety.com/_symposium/program.asp?i=7
y esta misma semana aparecen dos abstracs en la Journal ORG. Chemystri :
2006 Apr 28
IB-01212, a New Cytotoxic Cyclodepsipeptide Isolated from the Marine Fungus Clonostachys sp. ESNA-A009.
Cruz LJ, Insua MM, Baz JP, Trujillo M, Rodriguez-Mias RA, Oliveira E, Giralt E, Albericio F, Canedo LM.
Barcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain, Drug Discovery Division, Instituto Biomar S. A., 24231-Onzonilla, Leon, Spain, Proteomics Platform, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain, and Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain.
IB-01212, a new cytotoxic cyclodepsipeptide featuring C(2) symmetry, was isolated from the mycelium extract of Clonostachys sp. ESNA-A009. The amino acid sequence of the compound was determined by spectroscopy techniques. The absolute configuration of the amino acids was determined by a combination of the Marfey and menthol methods. The structure, which was confirmed by comparison of the analytical data for the natural product with a sample obtained by solid-phase peptide synthesis, was revealed to be a cyclic dimer formed by two chains of l-N,N-Me(2)Leu-l-Ser-l-N-MeLeu-l-N-MePhe bound by the two esters formed between the carboxylic acid of the l-N-MePhe and the hydroxyl function of the l-Ser. IB-01212 is highly cytotoxic to different tumor cell lines.
Traduccion :
Ib-01212, un cyclodepsipeptide citotóxico nuevo que ofrecía C(2) simetría, fue aislado del extracto del mycelium de los sp. Esna-a009 de Clonostachys. La secuencia del aminoácido del compuesto fue determinada por técnicas de la espectroscopia. La configuración absoluta de los aminoácidos fue determinada por una combinación de los métodos de Marfey y del mentol. La estructura, que fue confirmada por la comparación de los datos analíticos para el producto natural con una muestra obtuvo por la síntesis solid-phase del peptide, fue revelada para ser un dimer cíclico formado por dos cadenas de l-N, límite de N-Me(2)Leu-l-Ser-l-N-MeLeu-l-N-MePhe por los dos ésteres formados entre el ácido carboxylic del l-N-MePhe y la función del oxhidrilo del l-Ser. Ib-01212 es altamente citotóxico a diversas líneas de la célula del tumor.
2006 Apr 28
Total Solid-Phase Synthesis of Marine Cyclodepsipeptide IB-01212.
Cruz LJ, Cuevas C, Canedo LM, Giralt E, Albericio F
Barcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain, PharmaMar S.A.U., 28770-Colmenar Viejo, Spain, Drug Discovery Division, Instituto Biomar S. A., 24231 Onzonilla, Leon. Spain, and Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain.
A suitable combination of synthetic design, orthogonal protecting groups and coupling reagents was used to complete the first known synthesis of the natural marine cyclodepsipeptide IB-01212. The cyclic, symmetric octapeptide contains two of each of the following residues: l-N,N-Me(2)Leu, l-Ser, l-N-MeLeu and l-N-MePhe. IB-01212 also features two symmetric ester bonds between the hydroxyl group of Ser and the carboxyl function of the N-MePhe. Total solid-phase syntheses of the product was performed in parallel via three distinct routes: dimerization of heterodetic fragments, linear synthesis, and convergent synthesis. The convergent strategy gave the best results in terms of product yield and purity and is particularly suitable for the large-scale synthesis of IB-01212 and similar peptides.