Antitumor activity and distribution of pyrroloiminoquinones in the sponge genus Zyzzya.
A detailed analysis of four different collections of the sponge genus Zyzzya yielded nine pyrroloiminoquinones of the makaluvamine, batzelline, and isobatzelline/damirone classes. Dereplication analyses of additional Zyzzya extracts did not disclose more potent or additional new compounds. Comparative testing of these compounds in the National Cancer Institute's 60 cell line human tumor screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. Further studies on the topoisomerase II-mediated DNA cleavage were conducted. Reductive activation of the pyrroloiminoquinones led to DNA damage in vitro, which correlated with half wave potentials and reversibility parameters. DNA damage could be abrogated by ascorbate. Fluorescence displacement was used to measure intercalation with DNA; intercalation efficiency did not correlate with DNA-damaging proficiency. Makaluvamine H (5) emerged as the most potent and differential of our isolates, roughly comparable to makaluvamines C (in vitro) and I (in vivo). 3,7-Dimethyl guanine was isolated from one of the Zyzzya collections and from the sponge Latrunculia purpurea.
Dijoux
Marie-Geneviève
MG
Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, MD 21702-1201, USA.
Schnabel
Peter C
PC
Hallock
Yali F
YF
Boswell
Jamie L
JL
Johnson
Tanya R
TR
Wilson
Jennifer A
JA
Ireland
Chris M
CM
van Soest
Rob
R
Boyd
Michael R
MR
Barrows
Louis R
LR
Cardellina
John H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D047608:Pyrroloiminoquinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence
D000970:Antineoplastic Agents; D047608:Pyrroloiminoquinones; D004247:DNA