Aranciamycin analogs generated by combinatorial biosynthesis show improved antitumor activity.
Expression of the aranciamycin biosynthetic gene cluster in Streptomyces diastatochromogenes Tü6028 resulted in production of four novel compounds, aranciamycins E, F, G, and H with different decorations in the tetracyclic backbone. Two derivatives contain a D-amicetose moiety at C7 (aranciamycins F and G), two are hydroxylated at position C1 (aranciamycins E and G), and one is hydroxylated at C13 (aranciamycin F). Analysis of the biological activities of the aranciamycins against two human tumor cell lines--MCF-7 and MATU--shows surprising impact of the hydroxyl group at position C1 on activity. As aranciamycins E and G were the most active derivatives, hydroxylation of the C1 appears to coincide with increased antitumor activity of aranciamycins.
Albert-Ludwigs-Universität, Institut für Pharmazeutische Wissenschaften, Stefan-Meier-Strasse 19, Freiburg, Germany.
Andriy
A
Luzhetskyy
Jens
J
Hoffmann
Stefan
S
Pelzer
Sven-Eric
SE
Wohlert
Andreas
A
Vente
Andreas
A
Bechthold
D000595:Amino Acid Sequence; D018943:Anthracyclines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005818:Genetic Engineering; D006801:Humans; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013302:Streptomyces / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018943:Anthracyclines; D000970:Antineoplastic Agents; C075925:aranciamycin