Synthesis of Enediyne‐Chlorophyll Derivatives as Cytotoxic Conjugates.

Abstract

Conventional approaches to cancer treatment such as alkylating agents, platinum complexes, antimetabolites, and antitumor antibiotics are involved in cytotoxic intervention at the level of DNA replication. They act to block the biosynthesis or transcription of nucleic acids or to prevent cell division by interfering with mitotic spindles. While cytotoxic drugs are most effective against rapid growing tumor cells, they have the undesired property of inhibiting the synthesis of DNA in normal cells. Thus, there still remains a critical need for the development of agents possessing selectivity against tumor cells over normal cells. In view of non-specific cytotoxicity of most chemotherapeutic agents against normal cells, an efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit. One of the interesting approaches is a dyad conjugate targeting delivery of drug into the desired place via well-known ligand, which binds to receptors on the cells. Most targeted cytotoxic conjugates, such as siderophore-β-lactam, LHRH-doxorubicin, somatostatin-paclitaxel, and porphyrin-platinum(II) complex are hybrid molecules composed of a carrier and a cytotoxic moiety. A wide variety of porphyrin-based photosensitizers including porphyrins, chlorins, and bacteriochlorins have been used and suggested as photosensitizers in photodynamic therapy. The enigma of the selective accumulation of porphyrin into tumor site spurred exhaustive biomedical and photophysical studies. Such interesting biochemical properties of porphyrins prompted us to develop a new generation of enedyine-porphyrin conjugates. Over the past few years, intense research has been concerned with a new class of antibiotics, the enediynes, which are some of the most potent antitumor agents ever discovered. They contain a cis-hex-3-ene-1,5-diyne unit embedded within a strained 10-membered ring, which is capable of undergoing a cycloaromatization process to generate a benzenoid diradical. This diradical is capable of abstracting hydrogen atoms from the sugar part of DNA, which is responsible for DNA cleavage. Thus, we have interests in designing the structurally simplified enediyne unit hanging on porphyrin in a single entity. We reasoned that benefits of tumor-localizing porphyrin molecules are able to support selective tumorcidal action of enediynes. Here, we'd like to report the preliminary