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Published May 15, 1996 | Supplemental Material
Journal Article Open

A New and Unusual Pathway for the Reaction of Neocarzinostatin Chromophore with Thiols. Revised Structure of the Protein-Directed Thiol Adduct

Abstract

Neocarzinostatin (holo-NCS) is an antitumor antibiotic comprising a nonprotein chromophore component (1) and a 113- amino acid carrier protein (apo-NCS). Goldberg and coworkers first demonstrated that the reaction of the isolated chromophore (1) with thiols in the presence of double-stranded DNA leads to DNA cleavage by a free-radical mechanism. The pathway shown in Scheme 1 was later proposed to account for this activity, a proposal that is now supported by a considerable body of evidence. In 1992, Saito and co-workers showed that the reaction of holo-NCS with small thiols, such as β-mercaptoethanol (BME), takes a different course, to form a product that is formally a 1:1:1 adduct of thiol, 1, and water. Structure 2 was proposed for this adduct, along with the mechanistic pathway shown in Scheme 2. Complicating the analysis was the fact that 2 was an inseparable mixture of two components, present in equal parts.

Additional Information

© 1996 American Chemical Society. Received February 1, 1996. Publication Date (Web): May 15, 1996. We are grateful to Prof. Dennis A. Dougherty and Dr. James L. Gleason for insightful discussions and Dr. Scott B. Cohen for technical assistance in the early stages of this project. This work was generously supported by the NIH. S.P.A. gratefully acknowledges an NSF Pre-Doctoral Fellowship.

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