SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs

Abstract

Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5‐fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents are direct DNA‐modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme‐mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations.

Synthesis, in vitro cytotoxicity, and anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes

“…Dimers of more lipophilic compounds have shown potent and broad spectrum activity against human solid tumor cell lines both in culture and as xenografts in nude mice. Some of the bis-intercalators were found to possess high selective toxicity against human colon carcinoma (Yong et al, 2005;Denny, 2003). In addition to DNA intercalation, the bis-heterocyclic molecules were also shown to exhibit such diverse pharmacological activity as anti-microbial (Holla et al, 1998), anti-protozoal (Coro et al, 2005), anti-inflammatory (Sondhi et al, 2007), anti-HIV (Pomarnacka and Kornicka, 2001), and cytotoxicity (Antonini et al, 2008;Brana et al, 1997;Rewcastle et al, 1987;Gamage et al, 1999;Spicer et al, 2000;Dabholkar and Ansari, 2008).…”