Enediynes, characterization

Beginning in the 1980s research directed toward the isolation of new drugs derived from natural sources identified a family of tumor inhibitory antibiotic substances characterized by novel struc tures containing a C C—C=C—C C unit as part of a nine or ten membered ring With one double bond and two triple bonds (-ene + di- + -yne) these com pounds soon became known as enediyne antibiotics The simplest member of the class is dynemian A most of the other enediynes have even more compli cated structures... 

Enediyne antibiotics (Section 9 4) A family of tumor inhibit mg substances that is characterized by the presence of a C=C—C=C—C = C unit as part of a nine or ten membered nng... 

Van Lanen, S.G., Oh, T.J., Liu, W. et al. (2007) Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis. Journal of the American Chemical Society, 129, 13082. 

The starting points for both C1-C5 and C1-C6 cyclizations are characterized using C1-C6 distances to stress that starting point for both cyclizations is the same enediyne radical-anion. However, for transition states and products of C1-C5 and C1-C6 cyclizations, the respective incipient bond length (C1-C5 or C1-C6) was used as the reaction coordinate... 

Early attempts to generate and characterize m-benzyne (13) comprise the pyrolysis of 1,3-diiodobenzene (14) and the flash photolysis of benzenediazonium-3-carboxylate (15). " While in the former case only enediynes (16) were in accordance with the ionization potentials determined (pyrolysis temperature 960 °C), the results of the latter work remain unclear. A transient with m/z = 76 and a lifetime of 400 ps was observed, however, it was not possible to unambiguously identify this species as 13 due to the complexity of the product spectrum (Scheme 16.6). Indirect evidence for the existence of 13 stems from trapping experiments. ... 

The previously known kedarcidin chromophore (7) is revised to CCC (7559), and the mechanism of action of this enediyne has been studied (1560). The new maduropeptin chromophore 1601 was isolated from Actinomadura madurae, which is associated with a protein of 14 amino acids (1561-1563). The non-protein associated enediyne N1999A2 (1602) was characterized from Streptomyces sp. AJ 9493 (1564), and confirmed by synthesis (1565,1566). 

Murrell JM, Liu W, Shen B (2004) Biochemical characterization of the SgcAl a-D-gluco-pyranosyl-l-phosphate thymidylyltransferase from the enediyne antitumor antibiotic C-1027 biosynthetic pathway and overexpression of sgcAl in Streptomyces globisporus to improve C-1027 production. J Nat Prod 67 206-213... 

In 1993 shortly after 3 mm micro-probes became commercially available, an application of the use of 3 mm probe technology was reported by Hensens and coworkers at Merck.58 The enediyne antibiotic neocarzinostatin (9) is activated for duplex DNA cleavage by > 1000-fold by thiol reagents. Hensens and co-workers utilized both micro-inverse and micro-dual 3 mm NMR probes to characterize the structure and stereochemistry of the novel post-activated drug (10). 

This family of compounds, constituted mainly by a series of [7.3.1] derivatives, but including also [7.4.1], [8.3.1] and [9.3.1] polycyclic compounds, is characterized by the fact that the same synthetic strategy was followed for their preparation. That is, the formation of the cyclic enediyne system was achieved by the attack of the acyclic enediyne onto an aldehyde by one of the methods described above and illustrated in Scheme 19.17 for the formation of [7.3.1] systems. 

These predictions have been admirably fulfilled by the isolation and characterization of receptors themselves and by the assignment within receptors and individual molecules of domains responsible for such specific functions these include ligand binding, voltage sensitivity and effector coupling in ion channels and detection, initiation and delivery in the DNA cleaving enediynes (14,15). 

The three types of PKSs described here, the enediyne PKS, the C-0 bondforming PKS, and the AT-less PKS, are only representive examples that reside outside the archetypical PKS paradigms. Continued exploration on the mechanism of polyketide biosynthesis will undoubtly uncover more unusual PKSs. These novel PKSs, in combination with the archetypical ones, will ultimately enhance the toolbox available to facilitate combinatorial biosynthesis and production of iinnatural natural products. The full realisition of the potential embodied by combinatorial biosynthesis of PKSs for natural product structural diversity, however, depends critically on the fundamental characterization of PKS structure, mechanism, and catalysis. 

In addition to metal-yne n complexation, Pu and co-workers (522) synthesized and crystaUographically characterized a water soluble, metal-ene n-complex by reacting [Os(en)2H2H20] with a TMS-substituted enediyne (TMS=Tetramethylethylene). The X-ray structure shows q -enediyne complexation to osmium (Scheme 79), however, no metal-promoted Bergman cyclization reactivity is observed, and only enediyne dissociation occurs upon oxidation or photolysis of the metal complex. 

In this section, only enediyne antibiotics bearing an epoxy moiety will be treated. The enediynes are a class of natural products that consist of a unique molecular architecture and exhibit phenomenal antitumor activity. They are stmcturally characterized by an enediyne core containing two acetylenic groups conjugated to a double bond or incipient double bond within a nine-membered ring, such as neocarzinos-tatin 301, or a 10-membered ring, such as dynemicin A 304a. The enediyne cores... 

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