Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: three new products generated in the mithramycin producer Streptomyces argillaceus through combinatorial biosynthesis.
To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW. In this last step of the MTM biosynthesis, a keto group of the pentyl side chain is reduced to a secondary alcohol, and we anticipated the generation of an MTM derivative with an additional keto group in the 3-side chain. Insertional inactivation of mtmW, a gene located ca. 8 kb downstream of the mithramycin-PKS genes, yielded an S. argillaceus mutant, which accumulated three new mithramycin analogues, namely mithramycin SA, demycarosyl-mithramycin SK, and mithramycin SK (MTM-SK). The structures of these three compounds confirmed indirectly the proposed role of MtmW in MTM biosynthesis. However, the new mithramycin derivatives bear unexpectedly shorter 3-side chains (ethyl or butyl) than MTM, presumably caused by nonenzymatic rearrangement or cleavage reactions of the initially formed pentyl side chain with a reactive beta-dicarbonyl functional group. The major product, MTM-SK, was tested in vitro against a variety of human cancer cell lines, as well as in an in vitro toxicity assay, and showed an improved therapeutic index, in comparison to the parent drug, MTM.
Remsing
Lily L
LL
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 907 Rose Street, Lexington, Kentucky 40536-0082, USA.
González
Ana M
AM
Nur-e-Alam
Mohammad
M
Fernández-Lozano
M José
MJ
Braña
Alfredo F
AF
Rix
Uwe
U
Oliveira
Marcos A
MA
Méndez
Carmen
C
Salas
José A
JA
Rohr
Jürgen
J
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000494:pharmacology; D002240:Carbohydrate Sequence; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D014312:Trisaccharides / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D014312:Trisaccharides; D010088:Oxidoreductases; D008926:Plicamycin