Patent Watch

October 14, 2013

If handled carefully, enediynes make powerful cancer drugs. Inventors N. S. Chowdari, S. Gangwar, and B. Sufi synthesized enediyne compounds with general formula 1 that are based on the natural enediyne uncialamycin (2) scaffold (Figure 1). These compounds, used alone or in conjugates, are potent cytotoxins that may be useful in cancer chemotherapy.

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Enediynes are a class of natural antibiotics that are characterized by 9- or 10-membered rings that contain two C≡C bonds separated by a cis (Z)-substituted C=C bond. Enediynes can undergo Bergman cyclization to form 1,4-benzenoid diradicals, which abstract hydrogen atoms from other molecules. When the diradical is generated near DNA, it abstracts hydrogen atoms from the sugar backbone of the DNA molecule and results in single- and double-strand lesions.

The high reactivity of enediynes toward DNA makes them very toxic. Their potent activity may be beneficial, however, if they are used to target the DNA of cancerous tumors. Most enediynes inhibit the proliferation of various cancer cells, including those that resist other chemotherapeutic drugs. Several naturally occurring enediynes are in clinical trials against cancer.

Both epimers at C26 of the natural enediyne uncialamycin are active against several ovarian tumor cell lines, with IC50 values ranging from 9 × 10–12 to 1 × 10–10 M, depending on the epimer and the cell line or subline. The synthetic enediynes described by the inventors are derivatives of uncialamycin.

Using these toxic molecules demands specific delivery systems. Conjugates are innovative drug-delivery systems designed to target tumor cells precisely and minimize the risk of systemic toxicity. Typically, drugs are linked covalently to conjugates that act as targeting moieties, which specifically or preferentially bind to a chemical entity characteristic of the cancer cell.

The covalent linker is designed to be cleaved only by a factor that exists inside a cancer cell and not in plasma, so that the drug remains in an inactive form until it is released from the conjugate. A typical targeting moiety may be a polymer or an antibody. Polymer-conjugated and antibody-linked enediyne drugs such as gemtuzumab ozogamicin (Mylotarg) were used to deliver enediyne drugs to cancer cells. Mylotarg, however, has been withdrawn from the market because of high patient mortality.

General formula of compounds of the invention and natural enediyne uncialamycin

Compounds of structure 1 may be conjugated to a targeted moiety through a chemical bond to substituent R1. Compounds 3 and 4, shown in Figure 2, are examples of the synthetic enediynes with structure 1.

The investors tested the antiproliferative activities of several compounds against cancer cell lines. EC50 data for compounds 3 and 4 against 786-0 renal cancer cells and H226 lung cancer cells are shown in the table:

Example 786-0 cells,
EC50 (nM)
H226 cells,
EC50 (nM)
3 1.275 0.986
4 0.058 0.873

Several assays were also conducted on conjugates derived from other compounds of formula 1. (Bristol-Myers Squibb [Princeton, NJ]. WIPO Publication 2013122823, Aug 22, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

Representative examples of synthetic enediynes