Editorial [ Enediynes and Related Structures in Medicinal and Biorganic Chemistry Guest Editor: Ajoy Basak ]

Mother nature often provides scientists with new and innovative ideas. One perfect example is enediynes which have now become the core of research in cancer therapeutics. Enediynes are a group of cyclic natural molecules that consist of at least two triple bonds separated by a double bond in conjugation. These products of bacterial origin were first isolated in 1960s and have drawn special attention since mid-eighties following the discovery that they possess powerful antitumor antibiotic activity. The enediyne group is often called a “warhead” because it can easily cyclize to form aromatic ring system via a highly reactive 1,4 benzeniod diradical intermediate. This cyclization process is called the “Bergman cyclo-aromatization reaction” after the name of the discoverer (Bergman, R.G. Accts. Chem. Res., 1973). The diradical intermediate can cause oxidative cleavage to double stranded DNA, giving rise to enediyne's powerful antitumor activity. Depending on the nature of substitution and ring size, the above cyclization can be triggered by temperature, light, pH changes, catalyst, suitable donors, oxidative state, metal coordination/induction as well as transformation from one tautomeric form to the other. Other triggering methods such as release of ring strain, acid base induction and enzyme mediated cleavage of protecting group have also been demonstrated. Recently conditions have been developed for transformation of enediynes to fulvene and indene derivatives. Bergman cyclo-aromatization reaction proceeds more efficiently and under milder condition when enediyne system is present within a constrained cyclic (mostly 9 and 10 membered) system compared to the acyclic one. The size of the ring structure also plays a significant role on the ease of cyclo-aromatisation. Enediynes find very useful applications in the study of biological systems. Thus it is applied to the development of “catalytic antibody or Abzyme” and “novel anticancer agents”. So far four principle effects of the enediynes on mammalian cells have been identified. These are (a) Mutagenicity, (b) Antimitotic activity associated with cell-cycle arrest, (c) Apoptosis induction and (d) Differential induction. Overall enediynes act as antimitotic agents by inducing a temporary delay in the cell lines during division of nucleus and form an important class of antibiotics. So far there are reports of three types of natural enediynes: (i) Type I with 10-membered ring and a 3-ene-1, 5-diyne function eg. calicheamicin/dynemicin), (ii) Type II with 9-membered ring and a 3-ene-1, 5-diyne moiety e.g. kedarcidin and, (iii) Type III with 9-memdered ring containing a dienediyne function eg. neocarzinostatin. Calicheamicin/Dynemicin represent the most potent antitumor agents known. However they are limited by their high toxicity and selectivity. Several pharamaceutical companies including the Bristol-Myers Squibbs made significant contributions in this area. They developed dynemicin class of antibiotics that contain a hydroxyanthraquinone chromophore instead of sugar moiety as found in calicheamicin/esperamicin. Chromoproteins eg. C1027 (discovered in 1988/89) have proteins that wrap around the enediyne, which stabilizes it, and takes it out of the cell. The study of C1027 suggests that all enediynes share a common polyketide biosynthetic pathway. This opens the door to genetic manipulation of these biosynthetic pathways to develop new drug candidates with less toxicity. Of all the enediynes, only neocarzinostatin, which is a chromoprotein, is approved as a drug to treat liver cancer in Japan only. The United States has not approved such a drug. However calicheamicin is now heading most directly to clinical studies, compared to the rest of the enediynes. Efforts to attach calicheamicin to various drug antibody conjugates, peptides or steroids that seem suitable for clinical trials, make calicheamicin an enediyne of interest. Its derivative “Mylotarg” (an antibody conjugate) has now been approved for treatment of Acute Myeloid Leukemia (AML). This drug acts as targeted therapy by delivering the enediyne derivative directly to the cancer cells, thereby not affecting normal cells. Because of these developments enediynes have stimulated considerable synthetic interest, although their clinical use has been limited because of their modest selectivity for cancer cells. The biological mode of action occurs along one of two general pathways, depending on the type of enediyne structure. The majority of enediyne natural products, including calicheamicin undergo Bergman cyclization whereas others such as neocarsinostatin operates via a Myers-Saito pathway. In both cases the end result is cleavage of double stranded DNA leading to apoptosis. Enediynes remain as the major focus of chemists and biologists for future development of more useful and selective antitumor antibiotic drugs which may be useful to degrade harmful DNAs, Proteins, Enzymes and possibly other macromolecules. It is hoped that enediyne based antibiotics may one day be able to kill all types of cancer and bacteria including those of resistant type.