Plasticity in gilvocarcin-type C-glycoside pathways: discovery and antitumoral evaluation of polycarcin V from Streptomyces polyformus.
Gilvocarcin-type polyketide glycosides represent some of the most powerful antitumor therapeutics. Bioactivity-guided fractionation of a culture extract of Streptomyces polyformus sp. nov. (YIM 33176) yielded the known gilvocarcin V (2) and a novel related compound, polycarcin V (1). Structure elucidation by NMR and chemical derivatization revealed that the congener (1) features a C-glycosidically linked alpha-L-rhamnopyranosyl moiety in lieu of the D-fucofuranose. The concomitant production of two distinct furanosyl and pyranosyl C-glycosides that share the same aglycone is unprecedented in bacteria. A conversion of both isoforms via a quinone methide intermediate can be ruled out, thus pointing to two individual C-glycosylation pathways. Cytotoxicity profiling of polycarcin V in a panel of 37 tumor cell lines indicated significant antitumoral activity with a pronounced selectivity for non-small-cell lung cancer, breast cancer and melanoma cells. As the antiproliferative fingerprint is identical to that of actinomycin D, the known DNA interaction of gilvocarcins was established as a general principle of antitumorigenic activity.
Li
Yi-qing
YQ
Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Beutenbergstr. 11a, D-07745, Jena, Germany.
Huang
Xue-shi
XS
Ishida
Keishi
K
Maier
Armin
A
Kelter
Gerhard
G
Jiang
Yi
Y
Peschel
Gundela
G
Menzel
Klaus-Dieter
KD
Li
Ming-gang
MG
Wen
Meng-liang
ML
Xu
Li-hua
LH
Grabley
Susanne
S
Fiebig
Heinz-Herbert
HH
Jiang
Cheng-lin
CL
Hertweck
Christian
C
Sattler
Isabel
I
D000970:Antineoplastic Agents / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006027:Glycosides / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D013302:Streptomyces / Q000378:metabolism*
D000970:Antineoplastic Agents; D003374:Coumarins; D006027:Glycosides; C534478:polycarcin V; C031781:gilvocarcin V