Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin.
Neocarzinostatin (NCS) is an antitumor antibiotic comprising a 1:1 protein-chromophore complex and exhibits cytotoxic action through DNA cleavage via H-abstraction. Cytotoxic activity resides with the chromophore 1 alone, while the protein (apoNCS) protects and transports labile 1. The naphthoate portion (2) of NCS chromophore (1) is important for binding to apoNCS and DNA intercalation. In this paper we describe our attempts to use apoNCS to improve the hydrolytic stability of novel bifunctional DNA alkylating agents. The nitrogen mustards, melphalan and chlorambucil, were both conjugated to 2, and the biological activities of these conjugates were assessed. Chlorambucil did not benefit from conjugation. The melphalan conjugate (6) formed covalent DNA adducts at guanine bases and exhibited greater in vitro cytotoxic activity than unmodified melphalan. Fluorescence and NMR spectroscopy showed that 6 binds to apoNCS. Binding to apoNCS-protected 6 reduced the extent of hydrolysis of the conjugate. This novel approach demonstrates for the first time that an enediyne apo-protein can be used to improve the stability of substances that are of potential interest in cancer chemotherapy.
Urbaniak
Michael D
MD
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK.
Bingham
John P
JP
Hartley
John A
JA
Woolfson
Derek N
DN
Caddick
Stephen
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002699:Chlorambucil / Q000737:chemistry / Q000494:pharmacology; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008558:Melphalan / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019914:Taq Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009353:Zinostatin / Q000737:chemistry*
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil; D009353:Zinostatin; D019914:Taq Polymerase; D008558:Melphalan