Understanding and Exploiting Natures Chemical Arsenal: The Past,Present and Future of Calicheamicin Research

Abstract

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.

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

“…Calicheamicin is a naturally occurring enediyne antibiotic with high antileukemic potency and represents the clinically most promising candidate of this class of antitumor agents (Thorson et al, 2000). The tremendous potency of calicheamicin or its synthetic WII analog against leukemic cells is, however, accompanied by cytotoxic side effects.…”

Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

“…The positive charge is delocalized between the two N atoms, which withdraw electrons from H atoms and methyl group. The amidinium rest is positioned between two phosphate groups ( Figure 2) and therefore it is the question whether NH 2 or NMe group carries a larger positive charge. According to Mulliken or NBO charges, the NH 2 group does (0.40 vs 0.28 electron); however the methyl group has stronger contacts with the phosphate oxygen atoms than the NH 2 group.…”

A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis

“…C-1027 ͉ neocarzinostatin ͉ phosphopantetheinyl transferase T he enediyne antitumor antibiotics are among the most cytotoxic natural products ever discovered and have been actively pursued for their potential utility in cancer chemotherapy with two, calicheamicin (CAL) and neocarzinostatin (NCS), currently in clinical use (1)(2)(3). The enediynes have a common unprecedented structural feature accountable for their potent cytotoxicity: an enediyne core containing two acetylenic groups conjugated to a double bond, harbored within a nine-membered ring exemplified by C-1027, NCS, or maduropeptin (MDP) (Fig.…”