Understanding and exploiting nature's chemical arsenal: the past, present and future of calicheamicin research.
The enediyne antitumor antibiotics are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mode of action and many have spawned considerable interest as anticancer agents in the pharmaceutical industry. Of equal importance to these astonishing properties, the enediynes also offer a distinct opportunity to study the unparalleled biosyntheses of their unique molecular scaffolds and what promises to be unprecedented modes of self-resistance to highly reactive natural products. Elucidation of these aspects should unveil novel mechanistic enzymology, and may provide access to the rational biosynthetic modification of enediyne structure for new drug leads, the construction of enediyne overproducing strains and eventually lead to an enediyne combinatorial biosynthesis program. This article strives to compile and present the critical research discoveries relevant to the clinically most promising enediyne, calicheamicin, from a historical perspective. Recent progress, particularly in the areas of biosynthesis, self-resistance, bio-engineering analogs and clinical studies are also highlighted.
Thorson
J S
JS
Laboratory for Biosynthetic Chemistry, Memorial Sloan-Kettering Cancer Center and the Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA. jthorson@sbnmr1.ski.mskcc.org
Sievers
E L
EL
Ahlert
J
J
Shepard
E
E
Whitwam
R E
RE
Onwueme
K C
KC
Ruppen
M
M
D000475:Alkenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000494:pharmacology; D003001:Cloning, Molecular; D004249:DNA Damage; D008847:Micromonospora / Q000378:metabolism
D000475:Alkenes; D000480:Alkynes; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic